INTRODUCTION:The relentless surge of antimicrobial resistance (AMR) across bacterial, fungal, viral, and parasitic pathogens constitutes a catastrophic threat to global healthcare, rapidly rendering conventional organic anti-infectives obsolete and demanding the urgent development of innovative chemical scaffolds. AREAS COVERED:This expert opinion examines recent breakthroughs in bioorganometallic drug design. It evaluates the structural classification, multi-targeted mechanisms of action, non-canonical pathways, and preclinical efficacy of emerging organometallic compounds-specifically metallocenes, N-heterocyclic carbenes, half-sandwich arenes, and tricarbonyl complexes-combating drug-resistant infections. EXPERT OPINION:Organometallic platforms offer an unparalleled structural toolkit to overcome cross-resistance due to their modular geometries and ability to trigger simultaneous lethal mechanisms. To advance these candidates into human clinical trials and address lingering toxicity concerns, future research must prioritize optimizing the kinetic stability of metal-compounds networks to prevent premature in vivo speciation. Furthermore, integrating smart, pathogen-specific delivery vectors (such as peptide or antibody conjugates) will dramatically expand their therapeutic windows, facilitating the clinical translation of next-generation bioorganometallic anti-infectives.
BACKGROUND:Colorectal cancer (CRC) has become one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/β-catenin signaling is a crucial hallmark of CRC, and this pathway is involved in the development and maintenance of colorectal cancer stem cells (CCSCs). Therefore, inhibition of its activity may be an effective strategy for the treatment of CRC. METHODS:Based on the reported structural characteristics of LF3 which is a small molecule inhibitor of β-catenin/Transcription Factor 4 (TCF4) and the significant role of the naphthoquinone group in anti-tumor activity, we designed and synthesized a series of benzenesulfonamide derivatives. RESULTS:The results of anti-CRC activity showed that compound 3gg has anti-proliferation and anti-CCSCs activities by regulating the Wnt/β-catenin signaling pathway in vitro. In addition, compound 3gg could inhibit CCSCs activity through regulating the Wnt/β-catenin signaling pathway in xenografts. CONCLUSION:Compound 3gg, which inhibits CCSCs and Wnt/β-catenin signaling pathway activity, could be a promising lead compound for further investigation as a potential anti-cancer agent.
Heterocyclic scaffolds are vital to medicinal chemistry due to their versatility, diversity, and ability to target various biological molecules. This review covers advances in designing and synthesizing bioactive heterocycles, highlighting structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches with computational modeling and Artificial Intelligence (AI) to find potent, selective molecules with good Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profiles. Case studies show the successful development of heterocyclic drugs for cancer, microbial infections, inflammation, viral infections, and Central Nervous System (CNS) disorders. Synthetic methods have evolved from classical electrophilic/nucleophilic reactions to modern techniques like multicomponent reactions, microwave synthesis, metal catalysis, and green chemistry, making frameworks more accessible. The review discusses Quantitative Structure-Activity Relationship (QSAR) studies for molecular optimization. Challenges like synthetic complexity and resistance remain, but emerging trends like machine learning, omics, and enzyme synthesis offer new opportunities. Ultimately, combining design principles and innovative methods can speed up drug discovery and enable sustainable, personalized therapies with heterocyclic pharmacophores.
The global burden of cancer continues to escalate, with angiogenesis representing a critical driver of tumor progression and metastasis. Vascular endothelial growth factor receptor-2 (VEGFR-2) stands as the principal mediator of angiogenic signaling, making it an established and compelling therapeutic target. Despite the clinical success of first-generation inhibitors, their long-term efficacy remains limited by off-target toxicities, suboptimal pharmacokinetic profiles, and the inevitable emergence of drug resistance through multiple adaptive mechanisms. These limitations underscore an urgent need for next-generation inhibitors engineered with enhanced selectivity, improved safety margins, and the capacity to circumvent resistance pathways. This comprehensive review systematically examines recent advances in the rational design, synthesis, and biological evaluation of five-membered heterocyclic scaffolds, thiadiazol, oxazole, thiazole, and pyrrole, as well as pyrazole and imidazole-based inhibitors as novel VEGFR-2 inhibitors. Each section analyzes the molecular hybridization strategies employed to integrate essential pharmacophoric features, including heteroaromatic hinge-binding motifs, hydrogen bond donor-acceptor systems for DFG motif engagement, and terminal hydrophobic groups for allosteric pocket occupancy. Detailed structure-activity relationship discussions elucidate how substituent variations influence potency, selectivity, and physicochemical properties.
The epidermal growth factor receptor (EGFR) is a key regulator of malignant cell growth and survival, making it an attractive target for cancer therapy. In this study, a new series of thiazole derivatives was rationally designed and synthesized as potential EGFR inhibitors and evaluated for their antiproliferative activity against two human colon cancer cell lines (HCT-116 and HT29). Several compounds exhibited potent anticancer activity, with compound 4j showing the highest potency, displaying half-maximal inhibitory concentration (IC50) values of 2.10 and 1.91 µM against HCT-116 and HT29 cells, respectively. Owing to its superior antiproliferative activity, compound 4j was further evaluated for EGFR inhibitory activity and demonstrated remarkable potency with an IC50 value of 0.27 µM. In addition, 4j exhibited a favorable selectivity index toward normal WI38 cells and effectively induced apoptosis through modulation of Bax, Bcl-2, and p53 expression. Molecular docking demonstrated strong binding interactions of 4j within the EGFR active site, while its ADME predictions supported its favorable drug-like profile. Overall, compound 4j represents a promising lead candidate for the development of novel EGFR-targeted anticancer agents.
KRAS is one of the most frequently mutated oncogenes in human cancers, with KRAS G12D representing the predominant mutation in pancreatic ductal adenocarcinoma and a major driver of colorectal and lung cancers. Although KRAS was long considered "undruggable" due to structural and biochemical constraints, the discovery of the switch-II pocket enabled the development of direct KRAS inhibitors, leading to the clinical success of KRAS G12C-targeted therapies. Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805. Pan-RAS and pan-KRAS inhibitors have emerged as a promising strategy to overcome the limitations of mutation-specific KRAS inhibitors, including restricted mutation coverage and acquired resistance. Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.
Chromanone and chromone are related benzopyran-based scaffolds that offer multiple opportunities for structural modification and medicinal chemistry. This review summarizes studies published from 2020 to 2026 on the synthesis, structure-activity relationships, biological activities, and developability of these compounds in cancer and metabolic disorders. Recent synthetic approaches have enabled the modification of the heterocyclic ring, fused benzene ring, and carbonyl region, as well as the preparation of hybrid, fused, and spiro derivatives of these compounds. In anticancer research, these compounds have demonstrated antiproliferative, pro-apoptotic, cell cycle-modulating, and signaling-related effects. In metabolic disorders, the reported activities of these compounds include the inhibition of carbohydrate-digesting enzymes, improvement of insulin signaling, suppression of hepatic glucose production, and regulation of lipid metabolism. The review also evaluated the strength of the available evidence, noting that many studies remain limited to docking, isolated enzyme assays, or cell-based screening. The available information on physicochemical properties, pharmacokinetics, metabolism, safety, and in vivo efficacy is comparatively limited. Future research should prioritize standardized biological evaluations, robust mechanistic validations, and integrated optimization of potency, selectivity, safety, and pharmacokinetic properties to facilitate the translational development of chromanone- and chromone-based compounds.
AIM:A novel series of 2,7-disubstituted 6-methoxyquinazolin-4(3H)-one derivatives were designed, synthesized, and evaluated for in-vitro anti-cancer potential. METHODS:Compounds were docked, synthesiazed and then evaluated for in vitro anti-cancer activity using the sulforhodamine B assay in HCT116 and HepG2 cells. Apoptosis induction was analyzed via morphological changes, Hoechst 33342, and Annexin V/PI staining. The effect on β-catenin/TCF‑mediated transcriptional activity was assessed by TOPFlash/FOPFlash assay, TCF4 and β-catenin protein expression by immunocytofluorescence, and Wnt target genes (like c-MYC and Cyclin D1) mRNA levels by RT-PCR against HCT116 cells. Furthermore, In vitro anti-cancer potential was evaluated against primary human gallbladder cancer cells. RESULTS:The derivatives showed favorable binding with the active site residues on β-catenin and have the potential to disrupt the β-catenin/TCF4 interaction. Most of them have comparable anti-cancer activity to imatinib mesylate. Compound 42D, one of the potent compounds (IC50: 3.89 μM in HCT116; 8.28 μM in HepG2), induced apoptosis, and significantly downregulated β-catenin/TCF4 signaling and downstream targets (c-Myc, Cyclin D1) in HCT116 cells and this could be one of the mechanisms by which it exerts its anti-cancer activity. It showed anti-cancer activity in primary gallbladder cancer cells (IC50: 7.26 μM). CONCLUSION:Compound (42D) represents a promising molecule as an anti-cancer agent against colon, hepatocellular, and gallbladder cancers targeting the Wnt/β-catenin/TCF4 signaling pathway.
AIMS:Diabetes mellitus (DM) is a severe metabolic disease characterized by increased blood glucose levels due to reduced insulin action or secretion. This study aimed to synthesize new polyhydroquinoline (PHQ)-based acyl hydrazide derivatives and assess their potential as dual inhibitors of α-amylase and α-glucosidase enzymes. MATERIALS AND METHODS:Various acyl hydrazide derivatives of PHQ were synthesized via a multi-step reaction and structurally deduced through modern spectroscopic techniques. These compounds were evaluated for their in vitro studies, while molecular docking was performed to gain mechanistic insights into their biological activities. RESULTS AND DISCUSSION:In the series, compound (2c) emerged as the most potent inhibitor against both enzymes (IC50 = 0.44 ± 0.07 µM and 0.17 ± 0.01 µM, respectively), showing greater efficacy than acarbose. Density functional theory (DFT) analysis revealed valuable insights into the electronic properties and showed the best correlation with the biological targets. Moreover, molecular docking analysis showed good binding interactions with the active sites of both enzymes, which was supported by the experimental activities. CONCLUSION:These integrated experimental and computational results demonstrate that the polyhydroquinoline scaffold represents a promising platform for developing next-generation antidiabetic therapeutics with enhanced efficacy and favorable safety profiles.
Protein kinases are central regulators of cellular signaling and remain a major target class in precision medicine. While ATP-competitive inhibitors-including conformation-selective and covalent agents-have delivered substantial clinical benefit, durable responses are frequently limited by the conservation of the ATP pocket and the emergence of resistance mutations (e.g. gatekeeper and solvent-front substitutions), as well as kinase noncatalytic functions that are not addressed by enzymatic inhibition alone. Consequently, kinase drug discovery is expanding beyond orthosteric occupancy toward modalities that reprogram kinase conformations or eliminate the target protein. This Review summarizes the structural and medicinal chemistry principles underlying (i) allosteric inhibition and (ii) proximity-induced degradation, with an emphasis on design logic, structure-activity relationships, and key liabilities in the beyond rule of five space. We further highlight enabling technologies-including structural biology, chemical proteomics, and AI/ML-assisted modeling-that support allosteric site identification, ternary complex engineering, and multi-parameter optimization. Finally, we discuss translational challenges for bifunctional molecules, including permeability, exposure-response relationships, off-target degradation, and safety, and propose practical considerations for developing next-generation selective kinase therapeutics.
Cancer drug discovery is a complex process that requires identifying compounds that selectively target malignant cells. While high-throughput screening (HTS) is essential for testing large libraries, it generates vast datasets that are difficult to interpret. Recently, the integration of artificial intelligence (AI), particularly deep learning (DL), has significantly accelerated drug candidate selection. This review highlights the synergy between AI and HTS, emphasizing DL techniques such as convolutional neural networks for bioactivity prediction, recurrent neural networks for de novo design, and reinforcement learning for property optimization. These methods streamline preclinical research by enabling rapid multi-omics analysis and prediction of drug-target interactions. However, challenges regarding data quality, model interpretability, and ethics persist. Emerging paradigms like Explainable AI and federated learning aim to enhance transparency and collaboration while safeguarding privacy. Ultimately, overcoming these barriers through AI-HTS integration holds transformative potential to reduce development costs and improve clinical outcomes for cancer patients.
The quinoline nucleus is a privileged scaffold valued for its structural plasticity and synthetic accessibility. This review systematically summarizes advances in quinoline derivatives for targeted cancer therapy from 2017 to 2026, organized by major molecular target families - including kinases, metabolic enzymes, epigenetic regulators, drug transporters, and others - with emphasis on rational design, key structure-activity relationships (SARs), and antitumor efficacy. Despite progress, challenges such as isoform selectivity, suboptimal pharmacokinetics, and drug resistance persist; future efforts should focus on dual-targeting and prodrug strategies to overcome these limitations. This review aims to provide medicinal chemistry insights for the design of next-generation quinoline-based anticancer agents with improved selectivity, pharmacokinetic properties, and ability to overcome drug resistance.
AIM:Development of novel thioethers (5a-g), thioesters (6a-g), and bis-thioethers (8a-h) with antibacterial potential. MATERIALS AND METHODS:Twenty-one novel compounds were synthesized and evaluated for antimicrobial activity against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans. Compounds with significant antibacterial activity were estimated for antioxidant potential and in silico studies. RESULTS AND DISCUSSION:Eight of the tested compounds demonstrated significant antibacterial activity, particularly versus B. cereus and S. aureus. The minimum inhibitory concentration (MIC) revealed the remarkable antibacterial activity and bactericidal behavior, as demonstrated by minimum bactericidal concentration (MBC) determination and time-kill kinetics studies of 8g and 8h, against S. aureus. Moreover, both compounds exhibited notable antibiofilm activity against S.aureus. Selectivity of the tested compounds as antibacterial agents was confirmed by low cytotoxicity toward normal cells. Remarkably, compounds 8b and 8g exhibited antioxidant potential (ABTS and DPPH) assays in comparison to ascorbic acid. Evaluation of antioxidant markers revealed that 8g displayed an increase in superoxide dismutase (SOD) and malondialdehyde (MDA) level. In silico studies revealed that the compounds exhibited acceptable ADME properties, with strong binding to the bacterial dihydrofolate reductase active site, along with dynamic stability of the DHFR-8g complex.
AIMS:Antibiotic-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), have renewed interest in antivirulence strategies. This study aimed to design, synthesize, and evaluate asymmetric di‑heterocyclic benzazole derivatives as antibiofilm agents targeting wall teichoic acid (WTA) biosynthesis. MATERIALS AND METHODS:Twenty‑one novel bis‑heterocyclic benzazole derivatives bearing an ethyl‑thio linker were synthesized and characterized. Antibacterial activity was determined by broth microdilution. Antibiofilm activity (inhibition and eradication) was assessed at sub‑minimal inhibitory concentrations (sub‑MICs) using crystal violet. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed against key WTA enzymes (TarGH, TarS, TarM, TarL, and TarJ). RESULTS:Compounds 18, 21, 23, and 24 showed potent antibacterial activity against methicillin‑susceptible S. aureus (MSSA) and MRSA, with MIC values as low as 15.62 µg/mL. All selected compounds significantly inhibited biofilm at sub‑MIC levels. Compound 24 was most effective, with an MBIC50 of 3.90 µg/mL against MSSA and eradicated pre‑formed biofilms at 7.81 µg/mL. Docking and MD simulations revealed stable interactions of compounds 23 and 24 with TarGH and TarS, suggesting a WTA‑targeting mechanism. CONCLUSIONS:Di‑heterocyclic benzazole derivatives, especially compound 24, are promising scaffolds for antibiofilm agents against S. aureus. Our findings support further mechanistic and preclinical evaluation as potential antivirulence therapeutics.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.
Leishmaniasis is a neglected tropical disease, transmitted by the bite of infected female sandflies and affecting the poor population. Current pharmacotherapy has remained largely unchanged for decades, and there are parasitic strains resistant to these conventional treatments. Thus, there is an urgent need to identify molecular targets to guide the rational design of new drugs. Thus, cysteine protease B (CPB) emerges as a promising target due to its roles in pathogenesis, virulence, and in modulating the host immune response. Given this potential, this review presents recent advances in CPB inhibitors, examining scaffolds, their structure-activity relationships (SARs), and the structural elements that confer selectivity for the parasitic target. Aziridine analogs and dipeptidyl nitriles stand out, and the SAR studies presented here indicate that structural modifications in the P1, P2, and P3 binding subsites influence compound affinity, thereby optimizing molecular fit in the enzyme. The stereochemical configuration (S,S) of the inhibitors is also essential for potency. Regarding selectivity, the Tyr210 residue is present in CPB but not in human cathepsin L. Taken together, these structural and mechanistic findings offer new perspectives for advancing medicinal chemistry targeting CPB, in the development of safer, more selective, and more effective antileishmanial agents.
Novel 1,3,4-oxadiazole-2-thiol derivatives (8a-j) were synthesized via multistep reactions and characterized using IR, 1H NMR, and 13C NMR spectroscopy. The compounds were evaluated for dual anticancer and antibacterial activities through computational and experimental approaches. Molecular docking against EGFR (1M17) and DNA gyrase B (2XCT) revealed compound 8h as the most potent EGFR inhibitor (-7.528 kcal/mol), surpassing methotrexate (-7.448 kcal/mol), while compound 8c demonstrated superior DNA gyrase B binding (-7.263 kcal/mol), exceeding ciprofloxacin (-6.11 kcal/mol) by 19%. In vitro cytotoxicity against A549 human lung carcinoma cells identified compound 8c as the most active anticancer agent (IC50 = 14.59 ± 0.19 µg/mL), comparable to methotrexate (IC50 = 11.82 ± 1.22 µg/mL). Antibacterial screening against S. aureus, E. coli, and K. pneumoniae revealed compound 8d as the most effective broad-spectrum agent (MIC = 25 µg/mL across all strains), demonstrating 2-fold superior activity against S. aureus versus ciprofloxacin. Comprehensive DFT calculations on compound 8c elucidated frontier orbital energies (HOMO-LUMO gap: 4.7528 eV), global reactivity descriptors, optimized geometry, Mulliken charge distribution, and topological properties (MEP, RDG, ELF, LOL). ADMET profiling revealed favorable drug-likeness with 0-1 Lipinski violations, optimal lipophilicity (cLogP: 2.7-3.97), and good predicted oral absorption (57-64%). These findings establish 1,3,4-oxadiazole-2-thiol derivatives as promising dual-action therapeutic scaffolds.
AIMS:To develop effective functional ionic-liquid-related salts (ILRSs) as future anticancer drugs. MATERIALS AND METHODS:Twelve imidazole-based ionic-liquid-related salts were synthesized and characterized by spectroscopic methods. These ILRSs were used to study the antioxidant and anticancer activities, DNA titration, modeling, and in-silico studies. RESULTS:Among 12 ILRSs, ILRSs 5 and 4 indicated superior activities, showing higher scavenging percentages (70.7% and 65.5%) and lower IC50 values than the standard ascorbic acid. ILRSs 5 and 4 showed the most effective activities with MCF-7 cells, with viability values of 52.17% and 53.67% at 10 µM and IC50 values of 10.87 and 11.03 µM, respectively. DNA-binding studies showed moderate to strong interactions with Ct-DNA (binding constants: 104 to 105 M-1). The modeling studies of compounds A and B with DNA confirmed one hydrogen bond with -8.7 and -8.2 kcal/mol binding affinities. CONCLUSIONS:The reported ILRSs 5 and 4 showed good antioxidant and anticancer activities and may be used as future anticancer drugs.
