Tuberculosis remains the leading cause of death from infectious diseases worldwide, with an estimated 10.6 million new cases and 1.6 million associated deaths each year. The disease is caused by Mycobacterium tuberculosis, a bacterium that forms granulomatous lesions in the lungs and can exploit the body’s own protective structures to spread. Chronic pulmonary aspergillosis, a progressive fungal infection acquired through inhalation of conidia, affects an estimated 1.8 million people annually. Meanwhile, Escherichia coli has become the pathogen associated with the highest mortality rate linked to antimicrobial resistance, ranking in the highest quartile of the WHO’s 2024 Bacterial Priority Pathogens List. The researchers chose quinoline derivatives because this class of aromatic nitrogen heterocycles has demonstrated antimicrobial, antifungal, and antituberculosis properties, making them privileged structures in medicinal chemistry capable of modulating multiple biological targets.

The four compounds studied, designated QNL1 through QNL4, are derivatives of 1,4-dihydro-4-oxo-quinoline-3-carbohydrazide. QNL1 and QNL2 carry a chlorine atom at carbon 7 of the quinoline ring, while QNL3 and QNL4 have it at carbon 6. The phenyl ring attached through the carbohydrazide linker bears either two methoxy groups at positions C3 and C4 (QNL1 and QNL3) or three methoxy groups at C3, C4, and C5 (QNL2 and QNL4). These subtle differences in halogen position and methoxy substitution pattern proved to have measurable consequences for electronic behavior, molecular polarity, and predicted biological activity.

To characterize the electronic structure of each derivative, the team employed Density Functional Theory calculations using the B3LYP hybrid functional and the 6-311++G(d,p) basis set, implemented in the ORCA 5.0.4 program. The molecules were optimized both in vacuum and in dimethyl sulfoxide (DMSO) solvent, with the Conductor-like Polarizable Continuum Model (CPCM) used to account for solvation effects. From the optimized geometries, the researchers extracted frontier molecular orbital energies, the HOMO-LUMO energy gap, electronegativity, ionization potential, electron affinity, chemical hardness, softness, electrophilicity index, and nucleophilicity index. These conceptual DFT descriptors provide a quantitative framework for understanding molecular reactivity and predicting how the compounds might behave in biological environments.

The geometric optimization revealed that none of the four molecules adopts a completely planar conformation. The quinoline nucleus itself remains nearly planar, with an average angular deviation of only 0.266 degrees between the fused rings, but significant conformational variations arise from rotation of the substituent groups. The researchers validated their computational approach by comparing calculated bond lengths and angles against crystallographic data for a related quinolinium compound. The calculated C8-C7 bond lengths were 1.452 angstroms in DMSO and 1.459 angstroms in vacuum, compared to an experimental value of 1.368 angstroms, with the difference attributed to the replacement of a hydrogen atom by a carbonyl group in the derivatives. Average deviations between calculated and experimental parameters ranged from 0.010 to 0.091 angstroms in vacuum and 0.005 to 0.084 angstroms in DMSO, confirming the reliability of the computational method.

Analysis of the frontier molecular orbitals showed that the HOMO isosurface is predominantly distributed over the methoxy-substituted benzene ring and the N’-methylidenoformohydrazide chain in all derivatives, regions associated with electron density donation during electrophilic attack. The position of the chlorine atom on the quinoline ring exerts little influence on the most reactive region, since the HOMO is not significantly localized over the quinoline portion. However, the number of methoxy groups plays a critical role: as methoxy substitution increases, electronic density disperses more homogeneously over the benzene ring, reducing susceptibility to localized chemical attack. In DMSO, the solvent’s high dielectric constant spreads the HOMO over a broader region of the molecule and lowers its energy. The LUMO, conversely, is distributed mainly over the quinoline region in vacuum, with derivatives bearing more methoxy groups showing lower LUMO energies and greater capacity to accept electron density.

The ADMET evaluation employed multiple computational platforms including SwissADME, ADMETlab 3.0, admetSAR 3.0, pkCSM, Pred-hERG 5.0, StopTox, and the ADMET Prediction Service from the Laboratory of Molecular Modeling. QNL1 and QNL3 emerged as the leading compounds, both achieving oral bioavailability scores of 0.55 and demonstrating high intestinal absorption exceeding 95 percent. Their Caco-2 permeability values of approximately -4.92 in units of 10⁻⁶ cm/s indicate intermediate membrane penetration. Both compounds share identical molecular weights of 385.08 g/mol, topological polar surface areas of 92.78 square angstroms, and hydrogen bond donor counts of 2. Their logP values of 2.76 and 2.86 reflect a favorable balance between hydrophilic and lipophilic characteristics conducive to passive membrane diffusion.

Toxicity predictions revealed low cardiotoxic risk for both lead compounds, with hERG channel inhibition probabilities of approximately 0.08 for QNL1 and 0.06 for QNL3. The subtle difference in cardiotoxic risk between the two was attributed to the shift in chlorine position from ortho to meta on the quinoline ring. Both compounds showed moderate potential for CYP3A4 inhibition and moderate risk for drug-induced liver injury, warranting further experimental investigation. Acute toxicity predictions indicated low toxicity via inhalation, oral, and dermal routes, though both compounds showed a 65 percent probability of causing eye irritation or corrosion. The AMES toxicity test produced the highest predicted probability among all toxicological parameters evaluated, suggesting potential for DNA damage that must be confirmed experimentally before these compounds can advance.

Virtual target prediction using SwissTargetPrediction identified vascular endothelial growth factor receptor 2 (KDR) as the primary biological target for both QNL1 and QNL3, with association scores of 1300 and 1447 respectively. KDR is a high-affinity receptor tyrosine kinase crucial for angiogenesis and vascular permeability. In tuberculosis, granuloma formation creates local hypoxia that drives peripheral angiogenesis, and modulating the VEGF pathway may improve granuloma perfusion and reduce bacterial spread. The kinase class dominated the predicted target profile, increasing from 56 percent of predicted targets for QNL1 to 60 percent for QNL3, suggesting that the latter compound may exhibit greater selectivity while maintaining its primary mechanism of action.

The study concludes that QNL3 represents the priority candidate for further development as an oral drug, owing to its superior balance between systemic distribution and cardiovascular safety compared to QNL1. While QNL1 exhibits favorable physicochemical properties for absorption, QNL3’s metabolic profile and lower predicted cardiotoxic risk position it ahead in the ADMET framework. The preservation of pharmacophore characteristics across both lead compounds suggests structural elements compatible with interaction with VEGFR-2, justifying their inclusion in comparative analyses and additional screening. The researchers emphasize that these findings contribute to the rational design of new therapeutic strategies against tuberculosis, aspergillosis, and bacterial infections, highlighting the importance of integrating quantum mechanical calculations with predictive pharmacokinetic modeling in early-stage drug discovery.

Subject of Research: Computational mapping of electronic structure and ADMET properties of halogenated quinoline derivatives as potential antimicrobial and antituberculosis drug candidates

Article Title: Mapping the electronic and biological landscape of halogenated aryl quinoline derivatives via computational approaches

Article References: Sales, M. A., do Nascimento Gonçalves, C., dos Santos, A. L. S., da Rocha, M. N., Marinho, M. M., & Marinho, E. S. (2026). Mapping the electronic and biological landscape of halogenated aryl quinoline derivatives via computational approaches. Discover Chemistry, 3(1), Article 436. https://doi.org/10.1007/s44371-026-00886-0

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00886-0

Keywords: quinoline derivatives, DFT calculations, ADMET prediction, tuberculosis, drug discovery, KDR receptor, virtual screening, medicinal chemistry, antimicrobial resistance, hERG cardiotoxicity, molecular orbital analysis, oral bioavailability