The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure–activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents.

Background/Objectives: Antimicrobial resistance and bacterial persistence underscore the need to develop new chemotypes with multifunctional antibacterial mechanisms. This study aimed to design, synthesize, and evaluate curcumin-inspired 3,5-diarylidene-4-piperidones as versatile small molecules exhibiting antibacterial, antibiofilm, anti-efflux, DNA gyrase-inhibitory, and antiproliferative properties. Methods: A targeted series of triazole-conjugated 3,5-diarylidene-4-piperidones was synthesized through copper-catalyzed azide-alkyne cycloaddition click chemistry and subsequently characterized using standard spectroscopic techniques. The compounds were assessed for antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli. Selected active compounds underwent further evaluation for DNA gyrase inhibition, antibiofilm activity against multidrug-resistant S. aureus ATCC 33591, ethidium bromide accumulation, and antiproliferative effects on HCT116 and MCF7 cancer cells, with RPE1 cells serving as a control to evaluate cytotoxicity in normal cells. Additionally, computational studies, including QSAR analysis and molecular docking, were conducted to bolster structure–activity relationships and provide mechanistic insights. Results: Several derivatives demonstrated selective antibacterial activity against Gram-positive bacteria, particularly S. aureus, while exhibiting limited or no efficacy against E. coli. Compounds 7n and 7l emerged as the most potent against S. aureus, with minimum inhibitory concentrations (MICs) of 7.8 and 8.2 μM, respectively. Notably, compound 7l inhibited S. aureus DNA gyrase supercoiling, displaying an IC₅₀ of 3.20 μM, comparable to ciprofloxacin. Compound 7e exhibited the strongest antibiofilm activity against multidrug-resistant S. aureus, whereas compound 7a resulted in the highest accumulation of ethidium bromide, indicating robust anti-efflux activity. Antiproliferative assays revealed that select halogenated derivatives were effective against HCT116 and MCF7 cells, while the most promising antibacterial compounds exhibited minimal cytotoxicity toward RPE1 cells. Quantitative structure–activity relationship (QSAR) and docking studies supported the observed structure–activity relationships and suggested potential interactions with the ATPase binding site of DNA gyrase B. Conclusions: Triazole-conjugated 3,5-diarylidene-4-piperidones are promising multifunctional scaffolds with selective anti-S. aureus activity, antibiofilm and anti-efflux properties, and, for compound 7l, potent DNA gyrase inhibition. These findings support further optimization of this chemotype as a platform for developing antibacterial agents with polymechanistic activity.