Schiff bases, first reported by Hugo Schiff in 1864, form when a primary amine condenses with a carbonyl compound to create the characteristic azomethine, or HC=N, linkage. For more than a century and a half these molecules have served as workhorse ligands in coordination chemistry because their nitrogen, oxygen, and sometimes sulfur donor atoms grip metal ions with remarkable tenacity. The azomethine group is doubly important: it anchors the metal and it contributes directly to biological activity. Because the underlying aldehyde and amine building blocks can be swapped almost endlessly, chemists can tune the electronic and steric properties of the resulting ligands with fine precision, and decades of literature have documented antibacterial, antifungal, antioxidant, antiviral, antimalarial, anticancer, and anthelmintic behavior across this chemical family.

The research team, led by Md. Nur Amin Bitu and Md. Kudrat-E-Zahan at the University of Rajshahi with collaborators in Odisha and Riyadh, chose three amino acid precursors to build structural diversity into their ligand set. Salicylaldehyde was condensed with 6-aminohexanoic acid to give ligand L1, with L-arginine to give L2, and with DL-2-aminobutyric acid to give L3. Each condensation was carried out in a 3:1 ethanol-water mixture under reflux at roughly 80 degrees Celsius for four hours, yielding the lemon-yellow L1 at 92 percent, the yellowish-brown L2 at 93 percent, and the white L3 at 92 percent. The three ligands deliberately span an aliphatic chain, a guanidine-containing side group, and a short-chain architecture, allowing the team to probe how ligand structure governs both metal coordination and biological effect.

From these ligands the chemists generated eleven metal complexes. Ligand L1 yielded six: complexes of copper(II), manganese(II), cobalt(II), nickel(II), cadmium(II), and zirconyl(II), numbered 1 through 6. Ligand L2 produced nickel(II), cobalt(II), and manganese(II) complexes 7 through 9, while ligand L3 gave cadmium(II) and nickel(II) complexes 10 and 11. Synthesis relied on refluxing ethanolic solutions of the metal salts with the ligands, using a catalytic amount of potassium hydroxide as a deprotonating agent. The isolated solids were washed with diethyl ether and hexane and dried under vacuum, and elemental analysis confirmed purity, with carbon, hydrogen, and nitrogen deviations all within the accepted plus or minus 0.4 percent analytical tolerance.

Spectroscopy told the story of how the metals bind. In the free ligands, the azomethine stretching vibration appears at 1670 and 1634 inverse centimeters for L1 and L2 respectively; upon complexation this band shifts to between 1606 and 1641, a displacement of up to 64 inverse centimeters that signals coordination through the azomethine nitrogen. The phenolic O-H stretch likewise moved to lower frequency, and the asymmetric and symmetric carboxylate stretches shifted after complexation, demonstrating that the carboxylic oxygen also participates in binding. New medium-intensity bands between 597 and 673 and between 415 and 485 inverse centimeters were assigned to metal-oxygen and metal-nitrogen vibrations, the direct fingerprints of the coordination bonds. For ligand L3, the phenolic O-H position remained unchanged, indicating that in that ligand the phenolic oxygen stays out of the metal’s grip while the carboxylate and azomethine groups do the binding.

Electronic spectra and magnetic measurements then pinned down the geometries. Free L1 absorbs at 260 and 330 nanometers, corresponding to pi-to-pi-star transitions in the aromatic ring and n-to-pi-star transitions in the imine group; these bands red-shift and intensify upon metal binding as lone-pair electrons are donated to the metal center. New bands between 385 and 590 nanometers arise from metal-ligand charge transfer. Combining these data with effective magnetic moments, the team proposed octahedral geometries for complexes 1 through 3, tetrahedral geometries for complexes 4 through 9, and square-planar structures for complexes 10 and 11. The copper complex 1 shows a magnetic moment of 1.95 Bohr magnetons, consistent with a single unpaired electron in a Jahn-Teller distorted octahedral field, while the near-diamagnetic nickel complex 11 at 1.16 Bohr magnetons fits a square-planar d8 configuration. The authors are candid that single-crystal X-ray diffraction could not be obtained because the complexes are microcrystalline or amorphous, so these assignments rest on convergent but indirect spectroscopic and computational evidence.

Thermogravimetric analysis in nitrogen up to 800 degrees Celsius traced multi-stage decomposition pathways consistent with the proposed formulas. Complex 1 lost its carboxylate portions between 240 and 280 degrees Celsius with a 14.20 percent weight loss against a calculated 14.47 percent, and finally resolved to copper or copper oxide above 400 degrees. Complexes 2 and 3 decomposed in four stages beginning with lattice water loss around 50 to 180 degrees, and complexes 4 through 6 each released water, carboxylate, and organic fragments before collapsing to metal oxides between 450 and 630 degrees. The authors note that without complementary TG-MS or TG-FTIR techniques the decomposition assignments remain proposed rather than proven, an honest limitation they flag for future work.

Antibacterial testing by disc diffusion against Bacillus cereus, a Gram-positive strain, and Escherichia coli, a Gram-negative strain, revealed that complexation dramatically boosts activity compared with the free ligand. The cadmium complex 5 was the standout, producing a zone of inhibition of 32 plus or minus 0.26 millimeters against B. cereus, essentially matching kanamycin-30, and 24 plus or minus 0.26 millimeters against E. coli, below the antibiotic’s 29 plus or minus 0.10 millimeters. The copper complex 1 also performed well against both organisms. The team explains the enhancement through chelation theory: coordination reduces the polarity of the metal ion and delocalizes electron density over the chelate ring, raising lipophilicity so the complexes penetrate bacterial membranes more readily and reach intracellular targets such as DNA and enzymes. The authors stress that cadmium complexes require cytotoxicity evaluation against human cell lines before any therapeutic claim can be made, and that minimum inhibitory concentration testing was not performed, making these results preliminary and exploratory.

The computational arm of the study added mechanistic depth. Density functional theory calculations using the BP86 functional and def2-SV(P) basis sets in ORCA, with a conductor-like polarizable continuum model for water, showed that complex 5 has the most negative single-point energy of the series at minus 6299.1495 atomic units, marking it as the most thermodynamically stable, while complex 4 carries the largest dipole moment. The HOMO-LUMO gap of 2.571 electron volts and the highest chemical hardness of 1.2855 electron volts identified free ligand L1 as the most kinetically stable species, whereas complex 4, with the smallest gap and hardness, is the most reactive. Molecular docking against the 16S ribosomal RNA subunit of Thermus thermophilus, the same target through which kanamycin halts bacterial translation, showed that complex 1 achieved the strongest rRNA binding energy of the series, with the metal complexes generally matching or exceeding the affinities of kanamycin and pactamycin. The researchers caution that AutoDock Vina’s scoring function was developed for organic molecules and lacks validated metal parameters, so the docking results are qualitative indicators rather than mechanistic proof, and that complex 5 may act through additional targets such as membrane disruption. Together, the synthesis, spectroscopy, theory, and bioassays sketch a coherent picture of how simple amino acid-derived Schiff bases, when wrapped around the right metal, can become surprisingly potent antibacterial candidates.

Subject of Research: Transition metal complexes of salicylaldehyde-derived Schiff base ligands and their antibacterial activity

Article Title: Synthesis and antibacterial evaluation of transition metal complexes derived from salicylaldehyde based Schiff base ligands supported by DFT studies and molecular docking

Article References: Bitu, M. N. A., Uddin, S., Mohapatra, R. K., Azam, M., Mohapatra, P. K., Dash, G. C., Raval, M. K., & Kudrat-E-Zahan, M. (2026). Synthesis and antibacterial evaluation of transition metal complexes derived from salicylaldehyde based Schiff base ligands supported by DFT studies and molecular docking. Discover Chemistry, 3(1), Article 454. https://doi.org/10.1007/s44371-026-00900-5

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00900-5

Keywords: Schiff base, salicylaldehyde, transition metal complexes, antibacterial activity, DFT, molecular docking, coordination chemistry, kanamycin, 16S rRNA, cadmium complex, chelation theory, antimicrobial resistance

The team began with geometry. After fully optimizing the molecule without symmetry constraints and confirming through frequency calculations that the structure represented a true minimum on the potential energy surface, they obtained bond lengths and angles that tell a subtle electronic story. The sulfonyl S-O bonds came out at 1.441 and 1.449 angstroms, slightly shorter than the corresponding values in the antibiotic sulfadiazine, while the S-N bond of 1.699 angstroms sat between typical single- and double-bond lengths, a signature of resonance delocalization through the sulfonamide bridge. The authors attribute this enhanced orbital overlap to the electron-withdrawing fluorinated substituents and the fused heterocyclic ring, which pull electron density away from the sulfur center. Carbon-fluorine bonds ranged from 1.335 to 1.376 angstroms, reflecting fluorine’s powerful inductive effect, and aromatic carbon-carbon distances fell in the expected 1.37 to 1.42 angstrom window consistent with effective pi-conjugation.

Vibrational analysis reinforced the structural picture. The simulated infrared spectrum, scaled by the standard factor of 0.967, reproduced the characteristic fingerprint of an N-substituted sulfonamide: an intense N-H stretch at 3451 wavenumbers with an infrared intensity of 93.63 kilometers per mole, aromatic and aliphatic C-H stretches between 3104 and 2931 wavenumbers, coupled C-C and C-N ring vibrations near 1593 and 1542 wavenumbers, and the diagnostic asymmetric SO2 stretching band at 1328 wavenumbers. Each assignment, supported by potential energy distribution analysis, matched previously reported values for related heteroaromatic sulfonamides, validating both the optimized geometry and the computational protocol.

Nuclear magnetic resonance calculations added another layer of confirmation. Using the gauge-including atomic orbital method, the team computed carbon-13 shifts spanning 56.15 to 167.39 parts per million and proton shifts from 3.20 to 7.72 parts per million, then plotted them against empirical ChemDraw predictions. Most points clustered tightly around the line of perfect agreement, with modest deviations for carbons above 150 parts per million, where the quantum treatment explicitly accounts for geometry, electron density, and substituent-induced polarization. The most deshielded carbon, C19 at 167.39 parts per million, sits flanked by oxygen and nitrogen atoms within the triazolopyrimidine framework, while the most shielded, C32 at 56.15 parts per million, belongs to an electron-rich methoxy group.

The electronic heart of the study lies in the frontier molecular orbital analysis. Time-dependent DFT calculations across seven solvent environments, from gas phase to water, revealed three ultraviolet absorption bands at roughly 262, 277, and 298 nanometers, dominated by pi to pi-star transitions. The HOMO-LUMO gap ranged from 4.61 to 4.89 electron volts, with the largest value in water, where the high dielectric constant stabilizes the charge distribution through the polarizable continuum model. The orbital maps show electron density concentrated on the aromatic and sulfonamide donor regions in the HOMO and redistributed toward the electron-deficient triazine and fluorinated acceptor units in the LUMO, an architecture that drives efficient intramolecular charge transfer. Natural bond orbital analysis quantified this delocalization, with pi to pi-star stabilization energies reaching 51.49 kilojoules per mole and lone-pair donations from oxygen and nitrogen adding further stabilization.

Where the study turns genuinely eye-catching is in its nonlinear optical results. DTPB’s first-order hyperpolarizability came out at 1.5 times ten to the minus thirty electrostatic units, roughly eleven times higher than urea, the classic benchmark NLO material. Combined with a substantial total dipole moment of 8.5477 debye and a highly polarizable electron cloud, the molecule’s donor-acceptor architecture appears tailor-made for applications in optical switching, frequency conversion, photonic signal processing, and potentially LEDs, optical sensors, and solar energy technologies. The authors suggest that the same charge-transfer pathway that stabilizes the molecule electronically also amplifies its response to applied electromagnetic fields.

The team also brought mathematical chemistry to bear, converting DTPB into a molecular graph of 32 vertices and 34 edges and computing degree-based topological indices. First and Second Zagreb indices of 170 and 201, a Hyper Zagreb index of 878, and a Forgotten index of 476 all substantially exceed the values reported for the comparison molecule CMIO, confirming that the fluorinated substituents, sulfonamide group, and fused heterocycles create an unusually branched and interconnected topology. Such descriptors feed directly into quantitative structure-activity models that link molecular shape to biological and physicochemical behavior.

On the biological side, the picture is more sobering but scientifically coherent. Electrostatic potential maps pinpointed the sulfonyl and methoxy oxygen atoms as the primary electron-rich, hydrogen-bond-accepting sites, while the sulfonamide N-H proton emerged as the key electron-poor donor. Electron localization function and localized orbital locator maps confirmed the same heteroatoms as the principal reactive centers, and non-covalent interaction analysis showed that van der Waals contacts, not steric strain, dominate the molecule’s conformational stability. Docking simulations with AutoDock Vina against three protein targets produced favorable but moderate binding energies of minus 2.73, minus 3.26, and minus 4.17 kilocalories per mole, with the strongest interaction at the acetohydroxyacid synthase active site of protein 1YHY, each complex anchored by one hydrogen bond and a network of hydrophobic contacts.

Pharmacokinetic screening, however, tempered any drug-design enthusiasm. The Boiled-Egg model placed DTPB outside both the intestinal absorption and blood-brain barrier regions, consistent with its high topological polar surface area of about 125 square angstroms and moderate lipophilicity. The bioavailability radar showed acceptable size, flexibility, and saturation but flagged polarity and solubility as limiting factors, leading the authors to conclude that the molecule is better suited to peripheral rather than central nervous system applications, and that reducing polarity through structural modification could improve its profile.

Taken together, the study delivers something rarer than a single headline result: a complete, internally consistent digital twin of a complex fluorinated molecule, from bond lengths to binding poses. By showing that one computational framework can simultaneously predict spectra, quantify charge transfer, rank optical performance, and map biological recognition, the work offers medicinal and materials chemists a template for screening candidates before a single synthesis is attempted. The authors position their findings as a theoretical foundation for future experimental validation, molecular dynamics simulations, and the rational design of triazolopyrimidine-sulfonamide derivatives, whether the goal is a better crop-protection chemistry, a new photonic material, or simply a deeper understanding of how fluorine reshapes molecular electronics.

Subject of Research: Density functional theory investigation of the electronic structure, nonlinear optical properties, and bioactivity of the fluorinated triazolopyrimidine sulfonamide DTPB

Article Title: DFT investigation of 2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]triazolo[1,5- c ]pyrimidin-2-yl)-6-(trifluoromethyl)benzenesulfonamide (DTPB): Electronic structure, nonlinear optical response and bioactivity insights

Article References: Sasikala, L., Avinash, P., Suganthi, M., Suvitha, A., Britto, S., Vimal, S., & Prabhaharan, M. (2026). DFT investigation of 2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-6-(trifluoromethyl)benzenesulfonamide (DTPB): Electronic structure, nonlinear optical response and bioactivity insights. Results in Chemistry, 31, Article 103949. https://doi.org/10.1016/j.rechem.2026.103949

Image Credits: AI Generated

DOI: Not provided

Keywords: DFT, B3LYP, triazolopyrimidine, sulfonamide, fluorinated compounds, nonlinear optics, HOMO-LUMO gap, molecular docking, NBO analysis, molecular electrostatic potential, topological indices, pharmacokinetics

The study, published in Discover Chemistry, screened the Pan-African Natural Products Library, known as p-ANAPL, a curated collection of compounds derived from African medicinal plants. Rather than relying on docking scores alone, the researchers built a multi-stage pipeline that begins with ADMET filtering, which predicts how a molecule is absorbed, distributed, metabolized, excreted, and whether it poses toxicity risks. This approach acknowledges a hard truth in drug discovery: a compound that binds tightly but fails Lipinski’s Rule of Five, or blocks the hERG potassium channel critical for heart rhythm, is a dead end no matter how impressive its binding energy appears on paper.

The target protein was murine COX-2, taken from the Protein Data Bank under identifier 4PH9 at a remarkably high resolution of 1.81 angstroms. Crucially, this crystal structure contained ibuprofen bound in the active site, giving the team a known answer to validate their docking protocol. When they re-docked ibuprofen and compared the result to the original crystallographic pose, the heavy-atom root-mean-square deviation came out at just 0.85 angstroms, well below the commonly accepted 2.0 angstrom threshold. This gave the researchers confidence that their computational setup was faithfully reproducing the physics of drug binding in the COX-2 channel.

With the protocol validated, all 520 compounds in the p-ANAPL library were screened using a hierarchical approach: high-throughput virtual screening first, then standard precision docking to refine the top 33 candidates, and finally extra precision docking on the best five. Two molecules rose above the rest: 152CSB2 and Thix6g, both of which outscored ibuprofen in the extra precision ranking. The researchers emphasized that selection was not based on docking scores alone but on a combination of binding scores, interaction patterns with key residues, and ADMET acceptability, a more holistic criterion that reduces the risk of false positives.

Both lead compounds anchored themselves in the NSAID-binding channel through contacts with Arg-120 and Tyr-355, the catalytic gatekeepers that normally admit arachidonic acid. 152CSB2 formed three hydrogen bonds, including donor interactions with Arg-121 and Tyr-356 plus an acceptor bond with Met-523, along with a salt bridge to the guanidinium group of Arg-120, mirroring the classic binding mode of competitive NSAIDs. Thix6g, meanwhile, relied on two hydrogen bonds and a battery of aromatic interactions, including stacked pi-pi contacts with Tyr-356 and pi-amide contacts with Gly-527, suggesting a different but equally stabilizing strategy for occupying the pocket.

To confirm these poses were not fleeting artifacts of a static snapshot, the team ran 200-nanosecond molecular dynamics simulations using the Desmond package. The protein backbone of both complexes remained stable, with RMSD values hovering between 2.8 and 3.2 angstroms for 152CSB2 and around 3.0 to 3.2 angstroms for Thix6g. The ligand RMSD for Thix6g stayed remarkably close to its initial binding mode throughout the simulation, while 152CSB2 showed an initial adjustment period before settling into a stable configuration. Hydrophobic contacts between 152CSB2 and residues Tyr-356, Val-524, and Tyr-386 persisted for 32, 62, and 88 percent of the simulation time respectively, providing a dynamic picture of sustained binding that no single docking frame could capture.

Binding free energy calculations using the MM-GBSA method, performed on 400 equally spaced frames from the final 100 nanoseconds of trajectory, delivered the study’s most striking result. 152CSB2 posted a binding free energy of minus 32.12 kilocalories per mole, while Thix6g managed only minus 0.29 kilocalories per mole, a dramatic gulf that reflects fundamental differences in how the two molecules fit their target. The van der Waals contribution for 152CSB2 reached minus 16.97 kilocalories per mole against just minus 6.30 for Thix6g, pointing to superior steric complementarity. Thix6g was further penalized by high ligand strain energy and unfavorable desolvation costs, meaning the molecule had to contort itself into a less natural shape to squeeze into the active site.

The researchers then deployed density functional theory calculations at the B3LYP/6-311++G(d,p) level to probe the electronic personalities of the lead compounds. Both 152CSB2 and Thix6g showed lower ionization potentials than ibuprofen, meaning they donate electron density more readily, a property that could enhance their interactions with electron-poor residues in the COX-2 pocket. 152CSB2 also exhibited the smallest HOMO-LUMO gap at 0.28 atomic units, the highest softness, and the largest electrophilicity index, collectively marking it as the most electronically reactive of the three molecules. The frontier molecular orbital distribution for 152CSB2 spread across an extended aromatic system with a conjugated ethylenic bond, whereas Thix6g’s orbitals localized around oxygen-bearing phenyl groups, hinting at distinct mechanisms of electronic engagement with the protein.

Despite the promise, the authors are careful to frame these findings as computational hypotheses rather than proven drug candidates. MM-GBSA values are semi-quantitative ranking estimates, not experimentally measured affinities, and predicted ADMET profiles must be validated in the laboratory before any lead optimization can begin. The team also notes that the hierarchical HTVS-to-SP-to-XP screening workflow, though perhaps computationally unnecessary for a library of only 520 compounds, was retained as a scalable demonstration that can be applied to much larger African natural product collections in the future.

Nevertheless, the study represents a meaningful step toward harnessing Africa’s largely untapped botanical diversity for modern drug discovery. By combining rigorous structural biology, molecular dynamics, quantum chemistry, and pharmacokinetic filtering into a single pipeline, the researchers have shown that natural compounds from the continent’s medicinal plants can compete with, and in some respects outperform, blockbuster synthetic drugs like ibuprofen at the molecular level. 152CSB2, with its combination of stable binding, favorable ADMET characteristics, and distinctive electronic profile, now stands as the most compelling candidate for the in vitro and in vivo studies that will determine whether a digital lead can become a real medicine for inflammatory disease.

Subject of Research: In silico screening of the Pan-African Natural Products Library for selective COX-2 inhibitors

Article Title: In silico evaluation of p-ANAPL library against inhibiting the cognate isoform cyclooxygenase Cox-2

Article References: Gawoua Teumen, D., Amana, B. A., Eyia Andiga, L. G., Moto Ongagna, J., Amoa, P. P., Govender, K. K., & Bikele Mama, D. (2026). In silico evaluation of p-ANAPL library against inhibiting the cognate isoform cyclooxygenase Cox-2. Discover Chemistry, 3(1), Article 478. https://doi.org/10.1007/s44371-026-00924-x

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00924-x

Keywords: COX-2, p-ANAPL, molecular docking, ADMET, molecular dynamics, MM-GBSA, DFT, natural products, virtual screening, anti-inflammatory, drug discovery, inflammation

The stakes are higher than they might appear. Children are not simply small adults when it comes to chemical exposure. Studies cited by the research team indicate that children can ingest up to 24 milligrams of toy material per kilogram of body weight per day through mouthing behavior, making any leachable dye a genuine safety concern. Conventional synthetic colorants, particularly azo dyes, have long been scrutinized because they can release carcinogenic aromatic amines under reducing conditions. Regulatory frameworks such as the European EN 71-9/10/11 standards and the American ASTM F963 impose strict limits on toxic colorants in playthings, and the industry is actively hunting for alternatives that deliver vivid color without the toxicological baggage. Alizarin, with its centuries-long history of human use in cosmetics and consumer products, its natural origin in the root of the madder plant Rubia tinctorum, and its biodegradability, is an obvious candidate. What has been missing is a rigorous, quantitative description of the molecule’s electronic and optical behavior that could anchor such a substitution in hard science.

The research team, led by N. H. Vaosya and Rajveersinh Zala with supervision from Bharat Kataria and J. H. Markna, turned to density functional theory and its time-dependent extension, the workhorse methods of modern computational chemistry. Using the ORCA 6.1.1 software package with the B3LYP functional and the def2-SVP basis set developed by Weigend and Ahlrichs, they optimized the geometry of the alizarin molecule, which contains fourteen carbon atoms, eight hydrogens, and four oxygens arranged across three fused aromatic rings. The choice of basis set was deliberate: def2-SVP offers geometries within 0.01 angstroms of experimental structures while keeping the calculation tractable, requiring roughly twelve hours on a standard workstation for the 204 basis functions needed to describe the molecule. The optimization converged within eighteen cycles, and the resulting structure matched experimental X-ray crystallographic data with a root-mean-square deviation of just 0.023 angstroms, confirming a planar anthraquinone core with near-symmetric geometry.

That planarity is not a cosmetic detail. The flat, extended pi-conjugated system is precisely what makes alizarin a dye at all. Delocalized pi-electrons flowing across the three-ring skeleton create a small energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, and the calculations placed that HOMO-LUMO gap at 1.79 electron volts, with the HOMO sitting at minus 5.53 eV and the LUMO at minus 3.74 eV. This is squarely in the range needed for visible-light absorption, which typically requires gaps between 1.5 and 3.0 eV. The spatial separation of the two orbitals is equally telling: the HOMO concentrates on the electron-rich dihydroxy-substituted ring, while the LUMO spreads over the electron-poor carbonyl regions. This arrangement creates a classic push-pull architecture, with hydroxyl groups donating electron density and carbonyl groups accepting it, setting up a strong intramolecular charge transfer when the molecule absorbs a photon.

Time-dependent DFT calculations of the first thirty singlet-singlet transitions revealed exactly how that charge transfer plays out optically. The most intense visible absorption appears at 483.8 nanometers with an oscillator strength of 0.130, corresponding to a pi-to-pi-star transition from HOMO-1 to LUMO+1. Electron density difference maps showed roughly 0.38 electrons of charge shifting from the dihydroxy ring toward the carbonyl region upon excitation, a hallmark of charge-transfer character that explains both the molecule’s saturated color and its known solvatochromism, the way its absorption shifts by 15 to 25 nanometers in more polar solvents. The computed absorption maximum lands within three nanometers of experimental values measured in ethanol, and the derived molar extinction coefficient of approximately 2.95 times ten to the third liters per mole per centimeter agrees with measured anthraquinone data within eight percent. Translating the absorption into perceived color, the team calculated CIE chromaticity coordinates of 0.62 and 0.35, placing the dye firmly in the orange-red region that toy designers prize for its visual appeal.

The simulated spectra went further, dissecting the molecule’s vibrational and magnetic behavior. The calculated infrared spectrum reproduced the signature carbonyl stretch at 1668 wavenumbers, notably redshifted by 15 to 30 wavenumbers relative to isolated quinone carbonyls because of intramolecular hydrogen bonding between the ortho-hydroxyl groups and adjacent carbonyl oxygens. Those hydrogen bonds, with oxygen-oxygen distances of 2.56 to 2.59 angstroms and bond energies estimated at 12 to 15 kilojoules per mole, rigidify the molecule and reduce the HOMO-LUMO gap by about 0.15 eV, deepening the red color. Overall, the computed IR frequencies matched literature values with a correlation coefficient of 0.998 and a root-mean-square deviation of 9.8 wavenumbers. Gauge-including atomic orbital NMR calculations predicted carbonyl carbon signals separated by 8 to 10 parts per million, a diagnostic fingerprint that distinguishes alizarin from its isomer quinizarin, and a linear relationship between calculated carbon charges and chemical shifts emerged with a correlation coefficient of 0.92, consistent with Karplus-Pople shielding theory.

Mulliken population analysis added a quantitative picture of the molecule’s chemical personality. Oxygen atoms carry charges between minus 0.161 and minus 0.170 elementary charge units, while the phenolic hydrogens sit at plus 0.174 to plus 0.180, reflecting their acidity with a calculated pKa of 6.2. This polarization, producing a molecular dipole moment of 4.09 Debye, underpins two properties with direct relevance to interactive toys: alizarin’s ability to chelate metal cations through its catechol-like 1,2-dihydroxyanthraquinone motif, and its dramatic halochromic response. When deprotonated in basic conditions, the absorption band shifts by 40 to 60 nanometers toward 520 to 540 nanometers, flipping the color from orange-red to purple-red. The authors suggest this pH sensitivity and metal-binding behavior could enable educational and color-changing toys, and the same catechol binding motif has already made alizarin a candidate sensitizer for titanium dioxide photoanodes in dye-sensitized solar cells.

On the safety front, the team employed the U.S. Environmental Protection Agency’s Toxicity Estimation Software Tool, version 5.1.2, using consensus quantitative structure-activity relationship modeling. The predictions are encouraging: an acute oral LD50 exceeding 5000 milligrams per kilogram, no predicted mutagenicity, no skin sensitization potential, and existing regulatory approval by the FDA and EU authorities. Aquatic toxicity modeling predicted a fathead minnow 96-hour LC50 of 5.19 on the negative logarithmic molar scale, indicating moderate rather than acute hazard, with the model showing improved reliability for structurally similar compounds. The authors are candid about the limits of these in silico results, however. They emphasize that computational predictions are screening tools, not regulatory approvals, and that experimental validation including cytotoxicity assays, dermal irritation studies, and migration testing under EN 71-10/11 protocols remains essential before any toy bearing alizarin color reaches a shelf.

The study also flags genuine open questions. The team did not model how strongly alizarin binds to polymer matrices such as polyethylene or polypropylene, a critical gap given that poor dye-substrate affinity drives leaching and wastewater contamination. Photostability is another concern: experimental work has shown that alizarin degrades under ultraviolet light and chlorination into products including phthalic anhydride and benzoic acid derivatives, and transformation products can sometimes rival or exceed their parent compounds in toxicity. The researchers call for molecular dynamics simulations of dye-polymer interactions, systematic photodegradation studies identified through mass spectrometry, and full toxicological testing of degradation products. Even with those caveats, the convergence of a 1.79 eV electronic gap, a strong visible absorption at 483.8 nanometers, exceptional structural stability from intramolecular hydrogen bonding, and a favorable predicted safety profile positions alizarin as a scientifically grounded, environmentally sustainable alternative to synthetic azo dyes. A molecule first synthesized by Carl Graebe and Carl Liebermann in 1868, which helped launch the synthetic dye industry, may now help unwind some of its chemical excesses, one children’s toy at a time.

Subject of Research: DFT and TD-DFT computational analysis of the natural dye alizarin's photophysical properties and toxicological safety for toy applications

Article Title: Computational insights into Alizarin for toy applications using DFT calculations of photophysical properties and spectroscopic safety

Article References: Vaosya, N. H., Zala, R., Jadav, G., Katariya, D. K., Khunt, R., Kataria, B., & Markna, J. H. (2026). Computational insights into Alizarin for toy applications using DFT calculations of photophysical properties and spectroscopic safety. Discover Chemistry, 3(1), Article 482. https://doi.org/10.1007/s44371-026-00939-4

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00939-4

Keywords: alizarin, DFT, TD-DFT, toy safety, natural dyes, HOMO-LUMO gap, anthraquinone, intramolecular hydrogen bonding, QSAR toxicity prediction, sustainable manufacturing, UV-Vis spectroscopy, NMR chemical shifts

The significance of the target analytes is difficult to overstate. Hexavalent chromium, released into surface and groundwater by leather tanning, electroplating, pigment manufacturing and other industries, is a recognised carcinogen whose oxyanion species readily cross cell membranes and wreak oxidative damage on DNA and proteins. Ferric iron, while an essential nutrient, becomes a contaminant of its own when excessive concentrations stain water, promote the growth of iron bacteria in distribution systems, and, in biological contexts, catalyse the formation of hydroxyl radicals through Fenton chemistry, a process implicated in neurodegenerative disease pathology. Conventional detection of these ions relies on instrumental techniques such as atomic absorption spectroscopy or inductively coupled plasma mass spectrometry, which are accurate but expensive, laboratory-bound and poorly suited to real-time field screening. Fluorescent chemosensors offer an attractive alternative because the signal can be read with a simple spectrometer or even the naked eye under ultraviolet light.

The Indian team’s material is a marriage of two well-understood components. Polyaniline is the archetypal conducting polymer, prized for its reversible acid-base doping chemistry, environmental stability and intrinsic fluorescence, while sulfonated phenol formaldehyde is a water-soluble anionic resin whose sulfonate groups act as dopant and steric stabiliser at once. By polymerising aniline in the presence of varying amounts of the sulfonated resin, the researchers tuned the composition of the resulting composites, and the interplay between the conducting polymer backbone and the sulfonated matrix proved decisive for every property they measured. The composites were characterised exhaustively by Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, energy-dispersive X-ray analysis and thermogravimetric analysis, confirming successful composite formation and revealing how the resin content reshapes the polymer’s morphology and thermal behaviour.

Electrical conductivity measurements singled out one member of the family. The PANI–SPF 3 composite, with an intermediate resin loading, achieved a conductivity of 6.31 multiplied by 10 to the power of minus 3 siemens per centimetre, the highest in the series. This optimum reflects a classic doping balance: enough sulfonated resin to protonate and order the polyaniline chains into the electrically favourable emeraldine salt form, but not so much that the insulating resin dilutes the conductive pathways. The same intermediate composition also turned out to be the star performer optically and biologically, a coincidence the authors attribute to the density of accessible binding sites and the quality of the photophysical pathway within the material.

The sensing experiments were carried out in a dimethyl sulfoxide and water mixture, nine parts to one by volume, using ultraviolet-visible absorption and fluorescence spectroscopy. In the pristine state, the PANI–SPF 3 composite emits a measurable fluorescence signal. When aliquots of Cr6+ or Fe3+ are added, that emission is progressively extinguished, and the degree of quenching follows a linear Stern-Volmer relationship across the concentration range studied. Linearity in Stern-Volmer plots is the fingerprint of a well-behaved quenching mechanism, and it is what allows the intensity ratio to be converted directly into an ion concentration. The nanomolar detection limits derived from these plots represent an extraordinary amplification factor: a few hundred millionths of a gram of toxic metal per litre is enough to visibly darken the sensor’s output.

Several physical mechanisms can drive fluorescence turn-off in conducting polymer composites, and the authors discuss the likely contributors in terms of complex formation between the metal ions and the electron-rich nitrogen and sulfonate sites on the composite. Divalent and trivalent metal cations can coordinate to these sites, opening non-radiative decay channels or promoting photoinduced electron transfer that drains the excited-state energy before a photon can be emitted. Inner filter effects, in which the metal ion absorbs the excitation or emission light, may also contribute. The density functional theory calculations reported in the paper lend computational weight to this picture, modelling the complexes formed between the composite’s constituent units and the metal ions and clarifying why Cr6+ and Fe3+ quench so efficiently. The same computational framework was extended to rationalise the observed antimicrobial effects, connecting the electronic structure of the material to its biological activity.

The antimicrobial results are arguably the study’s most surprising dimension. All six composites were screened against Escherichia coli, a Gram-negative bacterium, and Staphylococcus aureus, a Gram-positive one, and PANI–SPF 3 again led the pack, producing zones of inhibition that the authors describe as notable in comparison with Gentamicin, a clinical antibiotic used as the reference standard. Conducting polymers have a growing reputation as antimicrobial agents, with proposed mechanisms including disruption of bacterial membrane potentials, electrostatic adhesion of the positively charged polymer backbone to negatively charged cell surfaces, and interference with electron transport across the membrane. The sulfonated resin component may add further activity by chelating essential metal ions from the microbial environment. A dual-function material that both reports contamination and suppresses microbial growth is an unusual and appealing combination for water treatment and packaging applications.

Safety is the perennial question for any material proposed for contact with drinking water, and the team addressed it directly. An MTT cytotoxicity assay, which measures the metabolic activity of cultured cells as a proxy for viability, showed that the PANI–SPF 3 composite is non-cytotoxic at concentrations up to 500 micrograms per millilitre. That margin provides a measure of reassurance for applications in which the sensor might contact potable water or come into contact with biological surfaces, although the authors are careful to frame this as an early-stage result rather than a regulatory clearance. The work also builds on the group’s own recent lineage of sulfonated-resin composites, including polyaniline and polypyrrole paired with sulfonated naphthalene formaldehyde and sulfonated melamine formaldehyde systems, which targeted chromium speciation, lead and mercury sensing, antifungal action and corrosion protection, suggesting a versatile materials platform rather than a one-off discovery.

What distinguishes this study within the crowded field of fluorescent heavy-metal sensors is the combination of sensitivity, simplicity and multifunctionality achieved with inexpensive, water-processable ingredients. Many high-performance chemosensors rely on elaborate organic syntheses, rare-earth dopants or quantum dots that complicate scale-up and raise their own toxicity questions. Here, the synthesis is a one-pot oxidative polymerisation in water, the characterisation is standard, and the resulting material conducts electricity, senses two priority contaminants at nanomolar levels, and kills bacteria on contact. The linear Stern-Volmer response means quantification requires nothing more exotic than a fluorescence spectrometer and a calibration curve, and the turn-off format, while inherently susceptible to false positives from other quenchers, benefits from the strong selectivity implied by the complexation chemistry and the DFT analysis.

The road from laboratory cuvette to field deployment remains long, as it always does for fluorescent sensors, with real water matrices, competing ions, pH variation and sensor regeneration all demanding attention. But the PANI–SPF work offers a compelling proof of concept that the humblest of industrial polymers, phenol formaldehyde chemistry dating back more than a century, can be re-engineered through sulfonation and combination with a conducting polymer into a twenty-first-century analytical tool. If subsequent studies confirm the selectivity in genuine environmental samples and establish long-term stability, composites of this kind could find their way into portable water-quality kits, smart packaging indicators and antimicrobial filtration membranes, turning the glow of a polymer film into an early-warning system for the contaminants that most threaten the world’s drinking water.

Subject of Research: Fluorescent PANI–SPF polymer composite chemosensor for detecting Cr6+ and Fe3+ ions in water with antimicrobial and DFT analysis

Article Title: Development of a polyaniline – sulfonated phenol formaldehyde (PANI–SPF) composite as a fluorescence ‘Turn-off’ chemosensor for Cr6+ and Fe3+ ions, antimicrobial application and DFT investigation

Article References: Rajeswari, M., & Kumar, K. K. S. (2026). Development of a polyaniline – sulfonated phenol formaldehyde (PANI–SPF) composite as a fluorescence ‘Turn-off’ chemosensor for Cr6+ and Fe3+ ions, antimicrobial application and DFT investigation. Polymer Bulletin, 83(12), Article 679. https://doi.org/10.1007/s00289-026-06738-2

Image Credits: AI Generated

DOI: 10.1007/s00289-026-06738-2

Keywords: polyaniline, sulfonated phenol formaldehyde, fluorescence chemosensor, hexavalent chromium, ferric iron, heavy metal detection, Stern-Volmer quenching, antimicrobial activity, DFT, water quality, conducting polymer, limit of detection

The biological target of the study is the central event in sickle cell pathology: the polymerization of hemoglobin S. The disease stems from a single point mutation in the beta-globin gene, in which glutamic acid at the sixth position is replaced by valine. When oxygen levels fall, this seemingly small change causes hemoglobin molecules to clump into rigid fibers, deforming red blood cells into their characteristic sickle shape. These rigid cells clog capillaries, a process known as vaso-occlusion, triggering painful crises, hemolysis and progressive organ damage. Repeated cycles of polymerization and depolymerization also generate oxidative stress, depleting nitric oxide in the vasculature and fueling inflammation that involves platelets, neutrophils and the endothelium.

Current therapies reflect the limits of treating a downstream process. Hydroxyurea raises fetal hemoglobin levels and reduces sickling, voxelotor binds hemoglobin reversibly to keep it in its oxygenated state, and crizanlizumab blocks platelet-mediated adhesion. L-glutamine offers antioxidant support, while regular transfusions manage severe cases. The only curative option, hematopoietic stem cell transplantation from a matched sibling donor, is limited by donor scarcity, cost and serious risks including graft-versus-host disease. Gene editing therapies are emerging but remain inaccessible to most patients globally. This therapeutic gap motivated the Indian team to search for small molecules that could directly inhibit hemoglobin S polymerization while simultaneously counteracting oxidative stress.

The researchers chose two pharmacophores with complementary biological credentials. The first is caffeic acid, a phenolic compound found in coffee, wine, tea and propolis, which has documented antioxidant, anti-inflammatory and anti-carcinogenic properties. Previous experimental work showed that caffeic acid increases the delay time for hemoglobin polymerization, a direct anti-sickling effect, and significantly lowers the concentration of ferryl hemoglobin formed during peroxide reactions. The second is phthalimide, whose derivatives, including the thalidomide family, have been shown to increase gamma-globin expression and fetal hemoglobin production while lowering tumor necrosis factor alpha, giving them both anti-sickling and anti-inflammatory potential.

Using an AI-assisted online tool called Mol-Opt, the team generated bioisosteric analogues of both scaffolds, systematically swapping functional groups to improve potency, pharmacokinetics and safety while preserving the molecular features responsible for activity. This yielded 373 candidate analogues across the two series. Each was then screened through a battery of computational filters. The ADMET Lab 3.0 platform predicted absorption, distribution, metabolism, excretion and toxicity parameters, while the Osiris Property Explorer provided drug-likeness and drug-score assessments. Encouragingly, every analogue satisfied Lipinski’s rule of five, the Pfizer rules and, with few exceptions, the Golden Triangle criteria, suggesting the designed molecules occupy drug-like chemical space with reasonable prospects for oral absorption.

The pharmacokinetic and toxicity screens narrowed the field considerably. Among the caffeic acid derivatives, compounds such as C-168, C-2, C-29, C-195 and C-27 stood out for combining high drug scores with low predicted toxicity. Analogue C-2 proved especially notable, showing the lowest hemotoxicity and genotoxicity values in its series. In the phthalimide series, P-60 and P-41 displayed excellent ADME balance with minimal tissue accumulation and very low skin sensitization, although several otherwise promising analogues, including P-155, P-171, P-202 and P-248, were rejected because of alarmingly high predicted genotoxicity, illustrating how computational toxicity screening can eliminate liabilities before any laboratory synthesis takes place.

The decisive test came from molecular docking against the crystal structure of deoxyhemoglobin S, available in the Protein Data Bank under the identifier 2HBS at 2.05 angstrom resolution. Using the Pyrex implementation of AutoDock Vina, the team docked the analogues into the hemoglobin active site and visualized the interactions with ICM Browser Pro. The phthalimide analogue P-2 achieved the study’s best binding affinity at minus 10.4 kilocalories per mole, followed by P-56 at minus 10.3. Among the caffeic acid derivatives, C-2 led with minus 9.0 kilocalories per mole, ahead of C-72 and C-68. For comparison, the approved drugs hydroxyurea, L-glutamine and voxelotor were docked under the same conditions, and the top analogues outperformed them, forming networks of hydrogen bonds and hydrophobic contacts with residues including LYS-66, ASN-102, ASP-99, VAL-98, LEU-28 and PHE-41.

Because a good docking score does not guarantee that a ligand remains bound in the dynamic environment of a real protein, the two lead compounds were subjected to 100-nanosecond molecular dynamics simulations using the Desmond package in the Schrödinger suite. The P-2 hemoglobin complex proved remarkably stable: after an initial equilibration period, the ligand’s root mean square deviation, fitted to the protein, settled within 1.2 to 2.2 angstroms and remained steady for the rest of the simulation. The C-2 complex showed somewhat greater fluctuation, with average protein RMSD values between 0.8 and 3.2 angstroms, but still maintained its binding pose within the active pocket. Contact analysis revealed that the ligands were held in place by a combination of hydrogen bonds, hydrophobic interactions and water bridges involving residues such as PHE-41, LYS-95, VAL-98, ASP-99 and GLU-43, providing a plausible structural basis for sustained anti-sickling activity.

To probe the electronic foundations of the two leads, the researchers performed density functional theory calculations using the ORCA 5.0.4 program at the B3LYP level with the def2-TZVP basis set. Compound C-2 displayed a HOMO energy of minus 8.63 electron volts localized over its catechol pi-system, identifying it as the principal electron-donating region, while its LUMO at minus 5.23 electron volts spread across the nicotinate ring and ester carbonyl groups. The resulting HOMO-LUMO gap of 3.40 electron volts indicates moderate electronic delocalization and efficient charge-transfer pathways, properties associated with reversible electron transfer and enhanced biological activity. Compound P-2 showed a smaller gap of 2.62 electron volts, with the HOMO distributed over its aromatic indole and benzoyl amide regions and the LUMO concentrated at the carbonyl nicotinate position, suggesting good conjugation and moderate chemical reactivity across the amide framework.

The authors conclude that the combined computational workflow, spanning bioisosteric design, ADMET prediction, docking, dynamics and quantum chemistry, has delivered two credible lead candidates, P-2 and C-2, that merit progression toward laboratory validation. Experimental studies to confirm their anti-sickling activity are reportedly underway. As with any purely computational study, the predictions remain hypotheses until synthesis, binding assays and animal or clinical testing are completed, and the high genotoxicity flags on several analogues underline the need for careful optimization. Nevertheless, the work demonstrates how a rational, multi-method in silico pipeline can compress the early stages of drug discovery, potentially cutting costs and timelines for a disease that has waited decades for a truly transformative small-molecule therapy.

Subject of Research: Computational screening of phthalimide and caffeic acid analogues as potential anti-sickling agents for sickle cell disease

Article Title: Computational screening of some newer potential anti-sickling compounds using docking, ADMET, DFT, and molecular dynamics approaches

Article References: Verma, D., Ahirwar, B., Vaishnav, Y., & Gahrewal, M. (2026). Computational screening of some newer potential anti-sickling compounds using docking, ADMET, DFT, and molecular dynamics approaches. Discover Chemistry, 3(1), Article 495. https://doi.org/10.1007/s44371-026-00942-9

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00942-9

Keywords: sickle cell disease, hemoglobin S polymerization, molecular docking, ADMET, molecular dynamics simulation, DFT, bioisosteres, phthalimide, caffeic acid, drug discovery, computer-aided drug design, vaso-occlusion

The team built a finite, hydrogen-terminated fragment of an armchair (5,5) single-walled carbon nanotube roughly 7 angstroms long, with a diameter of about 6.8 angstroms that makes the surface highly curved, and decorated one end with a carboxyl group. Using density functional theory with the M06-2X hybrid meta-GGA functional and the 6-311+G(d,p) basis set, a combination well benchmarked for hydrogen bonding and dispersion, they optimized the bare nanotube, the free isoniazid molecule, and a series of candidate adsorption complexes. Guided by the molecular electrostatic potential of isoniazid, which maps electron-rich and electron-poor regions of the drug, the researchers generated several chemically plausible starting orientations and let the optimizer decide which one nature would prefer.

The verdict was clear. Among six representative configurations, the lowest-energy arrangement bound isoniazid with an adsorption energy of −18.65 kcal per mole, or about −0.81 electron volts. That is dramatically stronger than the roughly 2 kcal per mole reported for isoniazid on pristine nanotubes, and it even edges out the 14 to 16 kcal per mole achieved with boron-doped tubes. The interaction still sits in the range associated with noncovalent adsorption, which is exactly what a drug carrier wants: strong enough to hold the payload, weak enough to release it inside a cell. Crucially, when the team repeated the optimization inside a polarizable continuum model of water, the adsorption energy softened to −13.38 kcal per mole but remained negative, meaning the complex stays thermodynamically favorable in an aqueous, body-like environment.

Thermodynamics told the same story from a different angle. At 298.15 kelvin and one atmosphere, the adsorption enthalpy was −16.65 kcal per mole in the gas phase and −12.67 kcal per mole in the implicit solvent, while the Gibbs free energy change was −7.40 and −3.39 kcal per mole respectively. Both negative enthalpies confirm the process is exothermic, and both negative free energies confirm it is spontaneous. The entropy change was negative in both environments, around −31 calories per mole kelvin, which simply reflects the loss of translational and rotational freedom when a free drug molecule locks onto a surface. Solvation barely touched the entropy term, indicating that water weakens the energetic driving force mainly by stabilizing the separated drug and nanotube rather than by changing how the complex forms.

To find out what physically holds the pair together, the researchers turned to the Quantum Theory of Atoms in Molecules, which examines the topology of the electron density between atoms. The analysis revealed two intermolecular bond paths in both the gas phase and water: one between a carboxyl oxygen on the nanotube and a hydrogen on the drug, and another between an N–H group of isoniazid and an oxygen of the nanotube’s carboxyl group. At each bond critical point, the electron density Laplacian was positive while the local energy density was negative, a signature of hydrogen bonds with partial covalent character. In other words, the drug is not just loosely clinging to the tube through vague dispersion forces; it is held by two specific, directional hydrogen bonds.

Natural Bond Orbital analysis quantified the electronic handshake behind those bonds. The dominant donor–acceptor interaction funnels electron density from the lone pair of the nanotube’s carboxyl oxygen into the antibonding σ* orbital of the drug’s N–H bond, with second-order stabilization energies of 12.78 and 7.21 kcal per mole for the two oxygen lone pairs in the gas phase. In water those values dipped to 10.50 and 6.31 kcal per mole, mirroring the weaker overall adsorption, but the same charge-transfer pathway survived. This is the classic electronic fingerprint of a hydrogen bond, and it dovetails perfectly with the QTAIM picture: adsorption proceeds by electron delocalization from the functionalized nanotube into the drug molecule.

Frontier molecular orbital analysis added a systems-level perspective. Isolated isoniazid has a generous HOMO–LUMO gap of 4.76 electron volts, but forming the complex collapses it to 1.74 electron volts in the gas phase and 1.51 electron volts in water, signaling substantially increased electronic delocalization across the drug–carrier interface. Meanwhile, the global hardness of the system rises from 0.40 electron volts for the bare nanotube to 0.87 electron volts for the complex, and electrophilicity falls from 14.54 to 7.05 electron volts, indicating that the assembled complex is electronically more stable and less eager to accept additional charge than the nanotube alone. Solvent polarization nudges these descriptors slightly, softening the complex and modestly raising its electrophilicity, but the overall electronic character established in vacuum persists in water.

Spectroscopy provided the final layer of confirmation. Gauge-including atomic orbital NMR calculations showed that the carbonyl group at the heart of the interface undergoes the largest electronic rearrangement: the isotropic shielding of the carbonyl carbon jumps from 9.77 to 24.87 parts per million upon adsorption, while the carbonyl oxygen’s shielding swings from −141.83 to 8.14 parts per million and its anisotropy plummets from 655.81 to 119.95 parts per million. The N–H group involved in the hydrogen bond also shifts, with its hydrogen’s isotropic shielding dropping from 26.39 to 21.62 parts per million. Calculated infrared spectra showed corresponding changes in C=O and N–H stretching frequencies, all consistent with a hydrogen-bonding environment reshaped by adsorption. Together, the energetic, topological, orbital, and spectroscopic lines of evidence converge on a single, coherent mechanism.

The authors are candid about the model’s limits. The calculations used a short, highly curved nanotube fragment with a single carboxyl group, so the reported energies are specific to this finite cluster rather than universal values for longer or multi-walled tubes. Chirality was not systematically varied, the conformational search was guided rather than exhaustive, and the implicit solvent cannot capture individual water molecules competing for hydrogen-bonding sites. The study is also entirely computational, awaiting experimental measurements of loading capacity, release behavior, and spectroscopic signatures. Still, the message is compelling: a simple carboxyl decoration transforms a weakly interacting carbon nanotube into a substantially stronger, thermodynamically spontaneous, water-stable carrier for isoniazid. If subsequent explicit-solvent simulations and laboratory tests bear this out, functionalized nanotubes could one day ferry higher, sustained doses of tuberculosis therapy directly to infected cells, easing the resistance problem one hydrogen bond at a time.

Subject of Research: Density functional theory investigation of isoniazid adsorption on carboxyl-functionalized (5,5) single-walled carbon nanotubes for drug delivery

Article Title: DFT investigation of the electronic structure, NMR parameters, and adsorption mechanism of isoniazid on carboxyl-functionalized (5,5) SWCNT

Article References: Hamedani, S., Shadi, M., & Moradi, M. (2026). DFT investigation of the electronic structure, NMR parameters, and adsorption mechanism of isoniazid on carboxyl-functionalized (5,5) SWCNT. Results in Chemistry, 31, Article 103916. https://doi.org/10.1016/j.rechem.2026.103916

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103916

Keywords: carbon nanotubes, isoniazid, drug delivery, DFT, hydrogen bonding, QTAIM, NBO analysis, NMR shielding, tuberculosis, nanomedicine, functionalization, computational chemistry

The research team designed ten new naproxen derivatives, labeled ND1 through ND10, by replacing the drug’s terminal carboxylic acid with an amide linkage attached to a variety of aromatic, heterocyclic, and aliphatic fragments. The naphthalene methoxy backbone that the cyclooxygenase enzymes recognize was left untouched, preserving the pharmacophore responsible for anti-inflammatory action. The logic is rooted in well-established medicinal chemistry: the acidic group anchors classical NSAIDs inside the COX channel through a salt bridge with the conserved Arg120 residue, but that same ionizable acid undergoes ion trapping in the acidic gastric lumen, directly irritates the epithelial barrier, and inhibits mitochondrial oxidative phosphorylation in stomach lining cells. Swapping the acid for a neutral amide could, in principle, keep the anchoring interactions while eliminating the gastric toxicity, and the amide’s terminal fragment could even reach into the less conserved side pocket that distinguishes COX-2 from COX-1, a strategy long used to convert non-selective NSAIDs into COX-2-preferring inhibitors.

To test this idea without synthesizing a single molecule, the researchers deployed a multi-layered computational pipeline. Density functional theory calculations at the B3LYP/6-31+G(d,p) level probed the electronic character of each derivative, yielding frontier molecular orbital energies, chemical hardness, softness, electronegativity, and electrophilicity. The results were striking: derivatives ND1 and ND4 showed the smallest HOMO-LUMO energy gaps, around 0.30 and 0.31 electron volts, compared with 0.87 electron volts for naproxen itself, indicating far greater electronic softness and reactivity. Soft molecules polarize more readily, which favors effective dispersion forces and electronic redistribution during non-covalent binding within the hydrophobic COX-2 pocket. ND2, meanwhile, posted the highest dipole moment at over 30 Debye, suggesting the strongest potential for polar interactions with the receptor. Molecular electrostatic potential mapping reinforced the picture, revealing that the high-polarization derivatives, including ND1, ND4, ND5, ND6, and ND9, retained sharply localized electron-rich and electron-poor regions capable of directional hydrogen bonding, effectively replacing the electrostatic role of the discarded carboxylic acid.

Before any binding predictions could be trusted, the docking protocol itself had to be validated. The researchers re-docked the co-crystallized ligands into the active sites of COX-1 and COX-2, using crystal structures 3KK6 and 3NT1 from the Protein Data Bank, and obtained root-mean-square deviations of 1.48 and 0.936 angstroms respectively, well within accepted thresholds. With the protocol confirmed, all ten derivatives were docked against both enzymes using AutoDock Vina and AutoDock4, alongside reference drugs including diclofenac, aspirin, mefenamic acid, and indomethacin. Every single derivative outperformed the parent drug. Naproxen scored roughly minus 7.5 kilocalories per mole against COX-2, while the derivatives ranged from minus 8.3 to minus 10.1 kilocalories per mole under Vina scoring. ND10, bearing an aminomethyl benzoic acid terminus, achieved the most favorable AutoDock4 score of minus 11.49 kilocalories per mole, driven largely by superior van der Waals contacts, while ND5’s bulky cycloheptylethyl group delivered a minus 10.43 kilocalories per mole result.

The docking poses revealed how the amide modification preserves potency through a clever molecular sleight of hand. Although converting the carboxylate into an amide removes the classical ionic salt bridge with Arg120, the amide carbonyl steps in as an alternative hydrogen-bond partner for the Arg120 guanidinium group in complexes ND3, ND5, and ND10. This neutral interaction, combined with deep penetration of the derivatives into the hydrophobic core near GLY526 and ALA527, provides a rational basis for COX-2 selectivity. Several complexes, including ND2, ND4, ND5, ND6, ND7, ND9, and ND10, reproduced the essential binding pattern of naproxen through pi-pi stacking with aromatic residues such as PHE381, TYR385, and TRP387, while ND4, ND6, and ND10 added hydrogen bonds and pi-sigma interactions with TYR385. By replacing the ionic anchor essential for COX-1 recognition with amide-based hydrogen bonding and expanded aromatic stacking, the derivatives exploit the larger active-site volume of COX-2 while potentially reducing the COX-1-mediated gastrointestinal harm of the parent acid.

Pharmacokinetic profiling through SwissADME and ProTox 3.0 added a crucial safety dimension. All ten derivatives fell safely below the 500 grams per mole Lipinski ceiling, satisfied hydrogen-bond donor and acceptor limits, and showed topological polar surface areas between 38 and 76 square angstroms, comfortably within the threshold for passive oral absorption. Predicted gastrointestinal absorption was high across the series, and all compounds were predicted non-cardiotoxic. The toxicity results were particularly encouraging: naproxen showed an LD50 of 248 milligrams per kilogram in toxicity class 3, whereas ND1 and ND8 exhibited LD50 values of 4000 and 5000 milligrams per kilogram in the far safer class 5. ND1, ND8, and ND10 were additionally predicted to be non-neurotoxic, and nearly all compounds showed inactive nephrotoxicity predictions, in contrast to active nephrotoxicity for naproxen itself. Caveats remain, however, as several analogues were predicted to inhibit multiple cytochrome P450 isoforms, flagging a potential risk of drug-drug interactions that will require experimental confirmation.

The three most promising candidates, ND2, ND4, and ND10, were then subjected to 100-nanosecond molecular dynamics simulations in GROMACS using the CHARMM36 force field, solvated in explicit water with physiological ion concentrations. The trajectories told a dramatic story. Naproxen repeatedly dissociated and rebounded at three distinct binding-site regions over the simulation, maintaining only intermittent hydrogen bonding of zero to two bonds and showing the highest conformational fluctuation of any system studied. ND4, by contrast, locked into its binding pose almost immediately and maintained a steady four to six hydrogen bonds, occasionally reaching seven, throughout the entire 100 nanoseconds. Its average root-mean-square deviation of 0.215 nanometers was the lowest of the series, and its solvent-accessible surface area of 255.90 square nanometers indicated the most compact, tightly bound complex. ND10 required roughly 50 nanoseconds to settle but then held its final pose with remarkable rigidity, achieving the steadiest plateau in the RMSD analysis.

Free-energy calculations using the MM/GBSA method over 501 trajectory snapshots quantified these differences with impressive precision. Naproxen’s binding free energy averaged minus 13 kilocalories per mole, while ND2 reached minus 16.5 and ND10 minus 25.4 kilocalories per mole. ND4 was in a class of its own at minus 46 kilocalories per mole, powered by an enormous van der Waals contribution of nearly minus 49 kilocalories per mole and an electrostatic term of minus 27 kilocalories per mole, reflecting its extended hydrogen-bond network with TYR324, ARG89, and ARG120. Per-residue energy decomposition confirmed that Arg120 contributed favorably to ND4 binding, demonstrating that the amide linkage had successfully recreated the anchoring interaction that the carboxylic acid once provided. Conformational analysis added a final layer of insight: 75 percent of the ND4 trajectory occupied a single conformational family, compared with only 43 percent for naproxen, whose energy landscape was fragmented across many shallow, poorly defined basins.

The authors are careful to frame these findings as exploratory rather than conclusive. Computational docking, dynamics, and ADMET predictions cannot fully capture the complexity of living systems, and predicted binding affinities do not always translate to in vitro or in vivo efficacy and safety. Experimental verification of the amide modification’s impact on cyclooxygenase selectivity, anti-inflammatory activity, metabolic stability, and gastrointestinal protection remains essential. Still, the study stands as a compelling demonstration of modern computer-aided drug design, showing how density functional theory, electrostatic mapping, validated docking, long-timescale simulation, and ensemble free-energy calculations can converge to identify ND4 and ND10 as lead candidates worthy of synthesis and biological testing. If laboratory work confirms what the simulations suggest, the humble painkiller in millions of medicine cabinets could one day be replaced by a safer, more potent descendant of itself.

Subject of Research: Computational design of naproxen amide derivatives as improved anti-inflammatory COX inhibitors

Article Title: Structure-based computational design of naproxen analogues with improved anti-inflammatory activity by DFT analysis, ADMET assessment, molecular docking, and molecular dynamics simulations

Article References: Abdullah, A., & Akhtar, M. (2026). Structure-based computational design of naproxen analogues with improved anti-inflammatory activity by DFT analysis, ADMET assessment, molecular docking, and molecular dynamics simulations. Results in Chemistry, 31, Article 103933. https://doi.org/10.1016/j.rechem.2026.103933

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103933

Keywords: naproxen, NSAIDs, COX-2 inhibition, computer-aided drug design, molecular docking, molecular dynamics simulation, DFT, ADMET, MM/GBSA, amide derivatives, gastrointestinal toxicity, drug discovery

Quinizarin, chemically known as 1,4-dihydroxyanthraquinone, is a planar aromatic molecule built around an anthraquinone backbone decorated with two hydroxyl groups. Its oxygen-rich framework gives it a natural affinity for metal ions with high charge density, and lithium — the smallest and most charge-dense metal ion in common use — is exactly the kind of target it should embrace. But while quinizarin’s coordination chemistry with heavier metals such as aluminum has been documented, its interaction with lithium had received little theoretical attention. A study published in the journal Ionics by Állefe Barbosa Cruz, Douglas Henrique Pereira and colleagues at the Instituto Tecnológico de Aeronáutica, the Universidade Federal dos Vales do Jequitinhonha e Mucuri and the Universidade Federal de Ouro Preto set out to fill that gap using quantum chemical simulation.

The team employed density functional theory, or DFT, the workhorse method of modern computational chemistry, to model quinizarin and its complexes with one and two lithium ions. Geometry optimizations and vibrational frequency calculations were carried out with the ωB97X-D functional, a long-range corrected hybrid functional that includes damped atom–atom dispersion corrections, combined with the 6–31+G(d,p) basis set. To mimic realistic conditions, the researchers used the SMD implicit solvation model to represent an aqueous environment — a sensible compromise, since explicit solvent molecules would have multiplied the computational cost without dramatically changing the dominant electrostatic effects. The absence of negative vibrational frequencies confirmed that every optimized structure sat at a true energy minimum.

The first striking result came from the frontier molecular orbital analysis. In the free quinizarin molecule, the highest occupied molecular orbital and its unoccupied counterpart are separated by a gap of just 1.63 electronvolts, a signature of a relatively reactive electronic structure. When a single lithium ion coordinates to the oxygen centers, that gap balloons to 6.50 electronvolts, and with two lithium ions it remains nearly as wide at 6.41 electronvolts. A large HOMO–LUMO gap generally signals chemical stability and reduced reactivity in the ground state. In other words, donating electron density to lithium stabilizes the dye so profoundly that its electronic personality changes almost completely — a transformation that could also be exploited optically, since frontier orbital energies govern the ultraviolet-visible absorption behavior that underpins cheap spectroscopic detection.

The structural changes tell the same story at the level of individual bonds. In uncomplexed quinizarin, the two carbonyl bonds measure 1.243 and 1.244 angstroms, in close agreement with experimental crystallographic values — the mean deviation between theory and experiment across the calculated bond lengths was only 0.008 angstroms, a testament to the accuracy of the chosen level of theory. When lithium binds, the interacting carbonyl bond stretches to 1.252 angstroms, a lengthening that reflects the loss of double-bond character as electron density flows toward the metal. Meanwhile, the carbon–carbon bonds adjacent to the new C–O–Li linkage contract, shortening to as little as 1.450 angstroms in the doubly coordinated complex. The newly formed oxygen–lithium bonds themselves measure between 1.870 and 1.879 angstroms. Together, these geometric shifts are the classic fingerprint of genuine chemical coordination rather than a fleeting, superficial contact.

To probe the nature of that bond at a deeper level, the researchers turned to the Quantum Theory of Atoms in Molecules, or QTAIM, a topological framework pioneered by Richard Bader that dissects the electron density distribution into chemically meaningful regions. QTAIM locates bond critical points along the pathways connecting bonded atoms and evaluates properties such as the electron density, its Laplacian, and the local energy densities at those points. For the oxygen–lithium interactions, the electron density at the bond critical points was high, the Laplacian was strongly positive — exceeding 149 kilocalories per mole per cubic bohr — and the total energy density was also positive, above 8 kilocalories per mole. That combination of signs is the textbook signature of a closed-shell, predominantly electrostatic interaction rather than a covalent one.

The energy density ratio -G(r)/V(r) came out at 1.37, comfortably above the threshold of 1.0 that distinguishes purely ionic, non-covalent interactions from partially covalent ones. The bond ellipticity values, ranging from 0.037 to 0.040, were close to zero, meaning the electron density around each bond path is nearly cylindrically symmetric — the hallmark of a well-defined, σ-type electrostatic bond with no significant directional strain. In plain terms, lithium is not sharing electrons with quinizarin so much as being seized by its oxygen atoms through powerful electrostatic attraction. That is precisely the kind of interaction one wants in an adsorbent designed to pluck lithium ions selectively from water.

The thermodynamics sealed the case. The binding energy for the mono-lithium complex came out at −10.74 kilocalories per mole, and for the di-lithium complex it nearly doubled to −20.57 kilocalories per mole, well beyond the −11.95 kilocalories per mole threshold (equivalent to −50 kilojoules per mole) conventionally used to classify an interaction as strong coordination. The Gibbs energy of complexation was negative in both cases — −3.77 and −6.98 kilocalories per mole respectively — confirming that the process occurs spontaneously in the modeled aqueous medium, while the enthalpy changes of −11.20 and −21.45 kilocalories per mole showed that the binding is exothermic, releasing heat as the complexes settle into their stabilized configurations. Doubling the lithium payload roughly doubles the energetic payoff, suggesting that quinizarin’s two oxygen-rich coordination sites can work in concert.

Why does this matter beyond the quantum chemistry? Lithium detection today relies largely on atomic absorption spectroscopy or flame photometry, both of which demand expensive instrumentation and demanding maintenance. Ultraviolet-visible spectroscopy offers a far more accessible alternative, and a ligand whose electronic structure shifts so dramatically upon lithium binding — a four-electronvolt widening of the orbital gap — is exactly the kind of molecular reporter that could translate lithium concentration into an easily measured optical signal. The same strong, spontaneous binding that enables sensing also underpins adsorptive recovery, in which a solid matrix decorated with quinizarin-like sites could capture lithium ions from brines or industrial wastewater for later release and reuse.

The authors are careful to frame the work as a fundamental computational investigation: DFT defines the scope and the limits of what can be claimed, and molecular-level descriptors are meant to guide, not replace, future laboratory experiments. Still, the convergence of evidence is compelling. Structural distortion confirms real coordination, frontier orbital analysis confirms electronic stabilization, QTAIM confirms a strong ionic bond, and thermodynamics confirms spontaneous, heat-releasing capture in water. As the pressure mounts to build sustainable lithium supply chains — from recycling spent batteries to extracting the metal from unconventional sources — simple, cheap organic molecules that grab lithium with both hands may prove to be among the most valuable tools in the chemist’s kit. Quinizarin, a dye that has colored fabrics for generations, may soon help color the lithium economy green.

Subject of Research: Density functional theory study of quinizarin–lithium ion complexation for lithium detection and recovery

Article Title: Computational Investigation of the Structural, Electronic, and Topological Properties of Quinizarin and Quinizarin–Lithium Ion (Li⁺) Complexes

Article References: Cruz, Á. B., Maciel, N. C., Leão, V. A., Sicupira, L. C., Leal, P. V. B., Ferreira, L. F., & Pereira, D. H. (2026). Computational Investigation of the Structural, Electronic, and Topological Properties of Quinizarin and Quinizarin–Lithium Ion (Li⁺) Complexes. Ionics. https://doi.org/10.1007/s11581-026-07568-y

Image Credits: AI Generated

DOI: 10.1007/s11581-026-07568-y

Keywords: quinizarin, lithium, DFT, QTAIM, coordination chemistry, lithium recovery, frontier molecular orbitals, computational chemistry, adsorption, battery materials, spectroscopic detection, sustainable mining

The biological rationale for targeting CDK1 is compelling. CDK1 is the master regulator of the G2-to-M transition in the cell cycle, the moment when a cell commits to dividing. Paired with cyclin B, it forms the M-phase promoting factor that phosphorylates the proteins responsible for chromosome condensation and spindle assembly. Unlike CDK2, CDK4, and CDK6, which show functional redundancy, CDK1 has no substitute at this checkpoint. Many tumors, particularly those carrying p53 mutations that cripple the G1 checkpoint, become dangerously dependent on CDK1 to enter mitosis even when DNA is damaged. Blocking CDK1 can therefore trigger mitotic catastrophe and apoptosis selectively in cancer cells, while normal cells with intact checkpoints pause and repair instead.

Despite this therapeutic logic, no CDK1 inhibitor has yet been approved by the FDA. Early pan-CDK inhibitors such as flavopiridel, now known as alvocidib, showed activity against leukemia and multiple myeloma but failed on selectivity, producing toxicity, diarrhea, nausea, and hepatotoxicity. Roniciclib trials in small-cell lung cancer were halted after severe adverse effects. Dinaciclib, which targets CDK1, CDK2, CDK5, and CDK9, remains the most clinically advanced agent, but the field continues to search for molecules with cleaner safety profiles. Natural products, which often carry lower intrinsic toxicity and can engage multiple pathways simultaneously, have emerged as an attractive hunting ground.

The research team turned to the NPACT database, a curated collection of plant-derived anticancer compounds, and focused on benzofuranoid phytochemicals from Morus alba. Rather than screening millions of synthetic molecules, they performed a targeted virtual screen of compounds with documented anticancer relevance. The CDK1 crystal structure, resolved at 2.33 angstroms and retrieved from the Protein Data Bank under the identifier 6GU6, was prepared in UCSF Chimera, and ligands were energy-minimized with the MMFF94 force field before docking with AutoDock Vina through the PyRx interface.

The docking results were striking. Mulberrofuran L bound CDK1 with a score of minus 8.5 kilocalories per mole, followed by mulberrofuran X at minus 8.2, mulberrofuran Y at minus 8.0, and euparin and 6-methoxy-tremetone at minus 7.7 each. Dinaciclib, the reference drug, scored only minus 6.6 kilocalories per mole. The docking protocol was validated by redocking the co-crystallized dinaciclib into the binding pocket, yielding a root-mean-square deviation of 1.38 angstroms, well below the 2-angstrom threshold that confirms a docking method reproduces known binding poses reliably.

Drug-likeness and pharmacokinetic filtering narrowed the field further. All five top compounds largely satisfied Lipinski’s Rule of Five, with the single exception of elevated lipophilicity: mulberrofuran L, X, and Y each showed logP values above 5, a violation the authors note may compromise aqueous solubility and oral bioavailability but does not automatically disqualify a compound. Predicted potency, estimated with the CODD-PRED server using machine learning models trained on curated bioactivity data, ranged from 5.28 to 5.48 in pIC50 terms, with mulberrofuran L scoring highest. The decisive filter was toxicity. ADMET profiling with the Deep-PK server flagged mulberrofuran Y, euparin, and 6-methoxy-tremetone for carcinogenicity and hepatotoxicity concerns, leaving mulberrofuran L and mulberrofuran X as the only candidates with clean toxicity profiles.

Those two survivors, along with dinaciclib as a benchmark, were then subjected to 200-nanosecond all-atom molecular dynamics simulations in GROMACS using the CHARMM36 force field. The mulberrofuran X complex proved the most stable of the three, showing the lowest and most consistent root-mean-square deviation at roughly 0.25 to 0.32 nanometers, the tightest radius of gyration at 2.32 to 2.36 nanometers, and the lowest solvent-accessible surface area, all signs of a compact, well-behaved protein-ligand complex. Mulberrofuran L fluctuated more, with RMSD values between 0.35 and 0.55 nanometers, though its excursions settled over time. Principal component analysis reinforced the picture: mulberrofuran X formed a tight conformational cluster, while mulberrofuran L sampled a broader range of motion along the first two principal components, and the free energy landscape confirmed that both compounds occupied well-defined low-energy minima rather than drifting into unstable states.

The energetic verdict was perhaps the study’s most eye-catching result. MM-GBSA binding free energy calculations, performed on frames extracted from the equilibrated trajectories, gave minus 15.66 kilocalories per mole for mulberrofuran X and minus 11.82 for mulberrofuran L, compared with just minus 2.31 for dinaciclib. Since more negative values indicate stronger binding, both mulberry compounds appeared to outperform the clinical reference by a wide margin in this metric. Density functional theory calculations added an electronic dimension: dinaciclib showed the smallest HOMO-LUMO gap at 2.894 electron volts, indicating the highest chemical softness and reactivity, while mulberrofuran L, at 2.943 electron volts, sat close behind, and mulberrofuran X, at 3.832 electron volts, was the most electronically stable of the three.

The authors are careful to frame these findings as hypothesis-generating rather than proof of therapeutic value. Every result in the study is computational, and the pipeline’s predictions, from pIC50 estimates to CYP450 inhibition flags for the mulberrofuran compounds, all require experimental confirmation. The team recommends in vitro kinase inhibition assays and cell viability tests such as MTT or CCK-8 to verify that mulberrofuran L and X actually suppress CDK1 in living cells, followed by cytotoxicity, selectivity, and mechanistic studies in cancer cell lines and eventually animal models. Predicted CYP inhibition in particular raises potential drug-drug interaction risks that only dedicated laboratory pharmacokinetics can resolve.

Even with those caveats, the study adds mulberry phytochemicals to a growing list of plant-derived CDK modulators, joining curcumin, wogonin, honokiol, and atractylenolide I, all of which have shown cell cycle arrest effects in preclinical cancer models. What distinguishes this work is the depth of the computational validation: a multi-level workflow spanning docking, dynamics, free energy, and quantum chemistry that converged on the same two candidates from different angles. If laboratory experiments bear out the simulations, the humble mulberry, a tree better known for feeding silkworms than fighting tumors, could yield lead structures for a class of cancer drugs that has long eluded medicinal chemists: selective, tolerable inhibitors of CDK1.

Subject of Research: Computational screening of Morus alba phytochemicals as CDK1 inhibitors for cancer therapy

Article Title: In silico investigation of mulberry phytochemicals targeting CDK1 in cancer using molecular docking and computational approaches

Article References: Abdullah, S., Nisar, S., Irshad, M., Saini, R. S., Alam, M., Ansari, I., & Junaid, M. (2026). In silico investigation of mulberry phytochemicals targeting CDK1 in cancer using molecular docking and computational approaches. Discover Chemistry, 3(1), Article 562. https://doi.org/10.1007/s44371-026-01020-w

Image Credits: AI Generated

DOI: 10.1007/s44371-026-01020-w

Keywords: CDK1, Morus alba, molecular docking, molecular dynamics simulation, phytochemicals, cancer, drug discovery, MM-GBSA, ADMET, DFT, mulberrofuran, cell cycle