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 clinical pedigree of the scaffold is difficult to overstate. Celecoxib, the archetypal COX-2 selective anti-inflammatory, ruxolitinib, the JAK inhibitor that transformed myelofibrosis care, and crizotinib, the ALK inhibitor that reshaped treatment of ALK-positive lung cancer, all carry the pyrazole core. According to the review, more than 30 pyrazole-containing drugs have been approved by the U.S. Food and Drug Administration since 2011, targeting diseases as varied as cancer, cystic fibrosis, HIV, rheumatoid arthritis and hereditary angioedema. Recent additions to that list include lenacapavir, a long-acting HIV capsid inhibitor; berotralstat, a kallikrein inhibitor for hereditary angioedema; and pirtobrutinib, a non-covalent BTK inhibitor designed for patients who have progressed on covalent predecessors. Each new approval reinforces the argument that the ring’s electronic configuration, hydrogen-bonding capability and conformational mimicry give medicinal chemists an unusually versatile handle on biological targets.

What explains this durability at the molecular level? The review devotes careful attention to the structural logic of the scaffold. Pyrazole’s aromaticity arises from delocalized pi-electrons across the five-membered ring, and the two nitrogen atoms exert a profound influence on polarity, dipole moment and reactivity. The N-H group acts as a hydrogen bond donor while the adjacent pyridine-like nitrogen serves as an acceptor, allowing the ring to engage enzymatic pockets in multiple orientations. Electrophilic substitution proceeds preferentially at C-4, while nucleophilic substitution favours C-3 and C-5, and tautomerism between the nitrogens adds a further layer of chemical adaptability. Because the ring can also serve as a bio-isostere for other aromatic systems, substituting pyrazole into a lead molecule often improves pharmacokinetic and pharmacodynamic behaviour simultaneously, a rare combination in scaffold-hopping exercises.

The heart of the review is its catalogue of newly synthesized derivatives and their measured activities, and the numbers are striking. Anwer and colleagues reported azobenzene-linked pyrazole-pyrimidine hybrids in which the leading compound achieved sub-micromolar cytotoxicity across four tumour cell lines, with IC50 values between 5.12 and 6.77 micromolar, while potently inhibiting VEGFR-2 at 0.90 micromolar and the resistant EGFR T790M mutant at 0.25 micromolar, outperforming erlotinib and matching sorafenib. Xu and co-workers fused pyrazole onto the natural product matrine, producing a derivative that killed Huh-7 hepatocellular carcinoma cells at 5.92 micromolar by inducing apoptosis, arresting cells in G0/G1 and suppressing JAK/STAT signalling in a dose-dependent manner. These are not incremental tweaks to known chemotypes; they represent deliberate re-engineering of how the scaffold engages intracellular machinery.

Selectivity, the perennial challenge of oncology drug design, emerges as a defining theme of the 2025-2026 cohort. Kou and colleagues built dihydropyrimidinone-pyrazole hybrids targeting the SHP2 phosphatase and achieved selectivity indices as high as 475.44 against MIA PaCa-2 pancreatic cancer cells relative to normal cells, meaning the compounds are hundreds of times more toxic to tumours than to healthy tissue. Fadaly’s group introduced oxime and nitrate moieties that enable covalent docking to the Cys797 residue of the double-mutant EGFR L858R/T790M, yielding IC50 values of 0.031 to 0.076 micromolar and selectivity windows comparable to osimertinib, the clinical standard for this mutation. Meanwhile, Abd El-Karim’s benzofuran-pyrazole hybrids displayed multi-kinase inhibition across B-Raf V600E, EGFR, VEGFR-2, c-Met and Pim-1 with GI50 values spanning 0.33 to 4.87 micromolar on the NCI-60 panel, all while remaining non-lethal to cells at much higher concentrations.

The review also highlights a delivery innovation that may prove as consequential as any single molecule. Aljohani and colleagues encapsulated pyrazole and pyrimidine derivatives within chitosan-polyvinyl alcohol nanogels and observed dramatic potency gains: cytotoxicity improved by 31.82 percent against A549 lung cancer cells, 40.12 percent against HCT116 colon cells, 50.00 percent against HepG2 liver cells and 52.61 percent against MCF-7 breast cancer cells, while all formulations retained IC50 values above 48 micromolar against normal VERO cells. The compounds function as topoisomerase-II inhibitors and DNA intercalators, and the nanogel vehicle appears to overcome transport barriers that limit intracellular entry of the free molecules. This pairing of rational small-molecule design with polymeric formulation points toward a hybrid strategy in which scaffold optimization and delivery engineering advance in lockstep rather than in sequence.

Infectious disease and agriculture feature prominently in the new data as well. Zalaru’s team achieved minimum inhibitory concentrations of 0.023 micrograms per millilitre against Staphylococcus aureus, an extraordinary potency figure, without cytotoxicity toward normal fibroblasts. Alenazi and Alnoman’s pyrazole-thiazole hybrids showed broad-spectrum inhibition of S. aureus, E. coli and Candida albicans with MIC values as low as 3.125 micrograms per millilitre, occasionally surpassing standard antibiotics, while Saadon’s 5-hydroxy pyrazole carbothioamide suppressed bacterial biofilm formation by 96.17 percent, on par with gentamicin. Keerthi’s pyrazole-oxadiazole hybrids matched ethambutol against Mycobacterium tuberculosis H37Rv with an MIC of 1.56 micrograms per millilitre. On the agricultural side, Huang’s benzophenone-linked pyrazole carboxamides outperformed the commercial fungicide bixafen against Sclerotinia sclerotiorum with an EC50 of 4.11 micrograms per millilitre, and Chu’s sulfonamide-oxadiazole hybrids beat boscalid against Valsa mali, disrupting hyphal ultrastructure and plasma membrane integrity in ways that translated to effective protection of apple fruits in vivo.

Metabolic and inflammatory pipelines show equally disciplined structure-activity logic. Sura and colleagues coupled pyrazole to isatin-triazole spacers to produce DPP-4 inhibitors, with the lead compound achieving 87.95 percent enzyme inhibition at an IC50 of 1.56 nanomolar, comparable to sitagliptin and teneligliptin, through pi-pi stacking with TYR666 and PHE357 in the active cavity. Elgohary’s sulfonamide celecoxib analogues inhibited COX-2 at 0.05 micromolar and, in a formalin-induced paw edema model, reduced TNF-alpha by 71.43 percent and PGE2 by 77.11 percent, outperforming both celecoxib and indomethacin with normal liver, kidney and cardiac parameters. Feng’s neuroprotective pyrazoles suppressed IL-6 expression in stimulated microglial cells at 9.562 micromolar, exceeding dexamethasone and celecoxib, offering a candidate for the secondary inflammation that follows spinal cord injury. Akocak’s arylazo pyrazole carboxamides, meanwhile, inhibited acetylcholinesterase with a Ki of 20.86 nanomolar, nearly eight times more potent than the reference drug tacrine, suggesting relevance to neurodegenerative disease.

The review’s authors argue that the field is undergoing a paradigm shift away from classical single-target analogue synthesis toward intentional multi-target-directed ligands, and they identify several frontiers that will define the next generation of work. Emerging designs include 5-aminopyrazole inhibitors of the deubiquitinating enzyme USP7, which drive p53-mediated tumour suppression, and tetrasubstituted 5-arylamino pyrazoles that arrest endothelial cell migration and tube formation by modulating intracellular calcium, offering selective antiangiogenic profiles without blind systemic cytotoxicity. Hybridization with HDAC-inhibiting aminobenzamides is proposed as a route around drug-resistance mechanisms. Looking ahead, the authors advocate systematically pairing automated, AI-driven QSAR models with polymeric nano-formulations and targeted protein degradation technologies such as PROTACs, a combination they believe can carry the pyrazole scaffold from academic screens into optimized, low-toxicity clinical and field-ready candidates. For a ring first celebrated more than a century ago in antipyrine, the 2025-2026 literature makes a compelling case that its most productive era may be the one just beginning.

Subject of Research: Biological evaluation of novel bioactive pyrazole derivatives in medicinal chemistry and agrochemistry

Article Title: Recent biological evaluations of novel bioactive pyrazole derivatives developed between 2025 and 2026

Article References: Patadiya, N., & Vaghela, V. (2026). Recent biological evaluations of novel bioactive pyrazole derivatives developed between 2025 and 2026. Discover Chemistry, 3(1), Article 520. https://doi.org/10.1007/s44371-026-00966-1

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00966-1

Keywords: pyrazole, medicinal chemistry, anticancer agents, EGFR inhibitors, COX-2 inhibitors, DPP-4 inhibitors, antimicrobial, agrochemicals, structure-activity relationships, drug discovery, nanogels, heterocyclic scaffolds

The scientific foundation of this approach rests on a deceptively simple biological observation. COX-2 is the inducible form of the cyclooxygenase enzyme, normally scarce in healthy tissue but rapidly upregulated during inflammation and, critically, in many premalignant and malignant lesions. The enzyme converts arachidonic acid into prostaglandins, most notably prostaglandin E2, which acts on a family of EP receptors distributed across tumor cells and the surrounding stromal and immune compartments. Through these signaling cascades, COX-2 activity promotes virtually every hallmark of malignancy: it drives proliferation, sustains survival pathways that block apoptosis, stimulates angiogenesis by upregulating vascular endothelial growth factor, and facilitates invasion and metastatic spread. Seminal work in the 1990s, including studies showing that COX-2 gene expression is elevated in human colorectal adenomas and adenocarcinomas, and that genetic or pharmacological inhibition of COX-2 suppresses intestinal polyposis in mouse models, established the enzyme as far more than an inflammatory bystander.

The review emphasizes that the strongest evidence for COX-2 targeted cancer prevention lies in colorectal neoplasia. Clinical trial data demonstrated that celecoxib significantly reduced the burden of sporadic colorectal adenomas compared with placebo, building on earlier findings that nonsteroidal anti-inflammatory drugs protect against colorectal cancer. The mechanistic explanation is increasingly well understood: prostaglandin E2 generated through the COX-2 pathway dampens antitumor immunity, skews the tumor microenvironment toward immunosuppression, and interacts with genetic drivers such as PIK3CA activation. Indeed, a retrospective analysis of the CALGB/SWOG 80702 trial reported improved disease-free survival with adjuvant COX-2 inhibition among patients with PIK3CA-activated stage III colon cancer, a finding the review highlights as a template for biomarker-guided patient selection. Observational cohorts in rheumatology have added circumstantial support, with chronic inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis associated with altered cancer risk profiles that implicate sustained prostaglandin signaling in tumor initiation.

Yet the same pathway that makes COX-2 inhibitors attractive in the colon also complicates their use elsewhere. The review documents a striking heterogeneity of responses across tumor types. In breast cancer, COX-2 overexpression marks aggressive stage III disease and experimental studies link the enzyme to metastatic behavior, including stabilization of E-cadherin adhesions through COX-2 and GSK3-beta signaling in metastatic models. In lung cancer, KRAS-driven COX2 expression has been identified through CRISPR-Cas9 screening as a driver of immunotherapy resistance, raising the prospect that COX-2 blockade could resensitize tumors to immune checkpoint inhibitors. However, randomized trials of celecoxib added to standard chemotherapy in advanced non-small-cell lung cancer, including the CALGB 30801 study which stratified patients by COX-2 overexpression, failed to demonstrate clear clinical benefit, and the NVALT-4 trial likewise found no advantage when celecoxib was added to docetaxel and carboplatin. These sobering outcomes underscore that COX-2 overexpression alone may be an insufficient biomarker, or that timing, dosing and tumor context determine whether inhibition helps or merely adds toxicity.

The pharmacological rationale for preferring selective COX-2 inhibitors over traditional NSAIDs begins with the gastrointestinal tract. Conventional NSAIDs inhibit both COX-1, which produces prostaglandins that protect the gastric mucosa, and COX-2, which drives inflammation. Dual inhibition therefore trades anti-inflammatory benefit for ulceration and bleeding risk, a well-documented liability in long-term use. Selective inhibitors spare COX-1 and thus preserve mucosal cytoprotection, a property confirmed in postoperative settings where meta-analyses found that selective COX-2 inhibitors did not increase gastrointestinal complications after colorectal cancer surgery. The clinical history of the class, however, carries a darker chapter: the withdrawal of rofecoxib and restrictions on valdecoxib following revelations of cardiovascular harm demonstrated that suppressing prostacyclin production while leaving thromboxane signaling intact tilts the hemostatic balance toward thrombosis. The review treats this cardiovascular toxicity as the central safety constraint, noting that dose-response relationships and careful patient selection, particularly in populations at elevated thrombotic risk, are non-negotiable prerequisites for any oncological application.

Beyond simple COX-2 blockade, the review catalogs an expanding repertoire of antitumor mechanisms that may operate independently of the enzyme itself. Selective inhibitors have been shown to modulate microRNAs that regulate oncogenic networks, to affect Wnt and NF-kappa-B signaling, and in some analogs to act through pathways entirely unrelated to cyclooxygenase, such as inhibition of PDK1 in the case of the celecoxib derivative OSU-03012. This pleiotropy cuts both ways: it enriches the therapeutic potential of the drugs but also complicates the attribution of clinical effects to COX-2 suppression alone. Experimental systems reinforce the complexity, with resistance mediators such as MFGE8 and KLK5/7 identified as drivers of breast tumorigenesis that can bypass COX-2 inhibition, suggesting that durable responses will require rational combination strategies rather than monotherapy.

Combination approaches feature prominently in the translational agenda the review lays out. Preclinical studies show that celecoxib augments paclitaxel-induced immunogenic cell death in triple-negative breast cancer models, potentially converting a cytotoxic regimen into an in situ vaccine. Nanoreactor formulations that co-deliver STING agonists with COX-2 inhibitors aim to simultaneously ignite innate immune sensing and extinguish the prostaglandin-mediated immunosuppression that blunts it. Dual inhibitors targeting both COX-2 and other enzymes such as 5-lipoxygenase, vascular endothelial growth factor receptor 2, carbonic anhydrase or epidermal growth factor receptor represent medicinal chemistry strategies to hit multiple tumor dependencies within a single molecule. Perioperative research adds another dimension: combining COX-2 blockade with beta-adrenergic signaling inhibition during surgery seeks to prevent the inflammatory and stress-driven environment that can seed recurrence, and clinical reports suggest that selective COX-2 inhibitors given for postoperative pain control in esophageal cancer patients may even prolong survival.

Drug delivery innovation offers a parallel route to widening the therapeutic window. Because much of the toxicity of COX-2 inhibitors is systemic, researchers are engineering formulations that concentrate drug exposure at the tumor site. Nanoliposomal encapsulation of celecoxib with genistein has been used to jointly inhibit the COX-2 pathway and GLUT-1 receptors in prostate cancer models, while chitosan nanoparticles loaded with diaryl pyrazole COX-2 inhibitors suppressed neoplastic growth through NF-kappa-B regulation in vivo. Nanovectors have shown promise in leveraging the chemopreventive potential of these agents against skin cancer, and gut-restricted selective COX-2 inhibitors have been explicitly designed to confine pharmacological activity to the colorectal lumen, minimizing plasma exposure and, with it, cardiovascular risk. Targeted imaging probes that bind COX-2, including near-infrared aggregation-induced emission probes and fluorescent sensors for hypochlorite monitoring, point toward a future in which the same molecular target enables both diagnosis and therapy.

The review’s authors frame the path forward as a series of open questions rather than a settled case. Which patients, defined by tumor genotype, prostaglandin pathway activity and cardiovascular risk profile, stand to benefit most? What doses and durations achieve antitumor efficacy without crossing into thrombogenic territory? How should COX-2 inhibitors be sequenced or combined with chemotherapy, targeted agents and immunotherapy to maximize synergy? The evidence assembled suggests that the era of prescribing these drugs indiscriminately for cancer prevention is over, but so too is the era of dismissing them. As precision oncology matures, biomarkers such as COX-2 and 15-PGDH expression in adenomas, PIK3CA mutation status and KRAS-driven inflammatory signatures may finally allow the inflammopharmacological insight at the heart of this drug class to be translated into safe, targeted clinical benefit.

The notion that anti-inflammatory drugs might influence cancer risk predates the COX-2 era by decades. Early observational studies of regular aspirin users suggested reduced colorectal cancer incidence, prompting international consensus statements that framed nonsteroidal anti-inflammatory drugs as plausible chemopreventive agents. Selective COX-2 inhibitors emerged from this lineage as an attempt to retain the antitumor benefits of prostaglandin suppression while shedding the gastric toxicity that limited long-term prophylactic use, particularly in older adults who bear the greatest cancer burden.

Medicinal chemistry continues to evolve around this target. Recent work has explored hybrid molecules that pair COX-2 inhibition with nitric oxide donation, aromatase blockade, or carbonic anhydrase suppression, aiming to exploit the enzyme’s frequent overexpression in tumors as a homing mechanism. Natural product research has likewise identified dietary and plant-derived compounds with COX-2 inhibitory activity, offering potential chemopreventive leads with more favorable safety profiles than synthetic coxibs.

Practical considerations of dosing in elderly patients, who often take cardioprotective aspirin alongside anti-inflammatory therapy, have driven interest in new formulations that reduce systemic exposure. Whether these strategies, together with biomarker-driven selection, can finally reconcile the anticancer promise of COX-2 inhibition with its cardiovascular liabilities remains the defining question for this pharmacological class in oncology.

Subject of Research: The role of cyclooxygenase-2 selective inhibitors in cancer prevention and therapy through modulation of inflammation, angiogenesis, apoptosis and antitumor immunity.

Article Title: Cyclooxygenase-2 selective inhibitors in cancer prevention and therapy: inflammopharmacological basis and translational prospects

Article References: Zhang, R., Tang, J., Wang, Y., & Fan, S. (2026). Cyclooxygenase-2 selective inhibitors in cancer prevention and therapy: inflammopharmacological basis and translational prospects. Medical Oncology, 43(10), Article 276. https://doi.org/10.1007/s12032-026-03395-3

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03395-3

Keywords: COX-2 inhibitors, celecoxib, cancer chemoprevention, prostaglandin E2, colorectal cancer, tumor microenvironment, immunotherapy resistance, cardiovascular toxicity, drug repurposing, nanomedicine, precision oncology, inflammation and cancer