In this study, ten derivatives of 2-iminothiazolidin-4-one were designed and synthesized as potential antagonists of the LasR protein, guided by extensive molecular docking studies and molecular dynamics simulations (MDS). The synthesized compounds were assessed for their antimicrobial activity and the potential as quorum sensing (QS) inhibitors against Pseudomonas aeruginosa by targeting biofilm formation and associated virulence factors such as pyocyanin, rhamnolipids, protease, and hemolysin. Among these, compounds 8f, 8 g, and 8h showed significant inhibition of P. aeruginosa biofilm formation with percent inhibition of 88.87 %, 87.74 %, and 88.77 %, respectively, compared to azithromycin 66.6 %. Further studies demonstrated that 8f, 8 g, and 8h exerted QS inhibitory activity of P. aeruginosa (in sub-MIC) pyocyanin, rhamnolipid, protease, and hemolysin and rhamnolipid inhibition assays with inhibition percentages ranged from 73.86 % to 85.40 % surpassing the inhibition observed with azithromycin (54–69.91 %). Further evaluation for the most active analogs, compounds 8f, 8 g, and 8h, using an in vitro LasR inhibition assay, revealed IC₅₀ values of 1.45, 1.38 and 1.22 μM, respectively. Additionally, extensive in-silico and molecular dynamic experiments showed that compound 8f exhibited strong interactions with the LasR ligand-binding pocket, leading to the complete dissociation of the protein's dimeric form over approximately 400 ns of MDS. This confirms its action as a LasR inhibitor. These findings establish a robust functional model for LasR inhibition and highlight the potential of 2-iminothiazolidin-4-one derivatives as promising QS modulators for combating P. aeruginosa infections.

Benzimidazole derivatives have garnered significant attention in medicinal chemistry owing to their versatile pharmacological properties, particularly their potent antimicrobial activity. This review comprehensively explores the advancements in the synthesis of benzimidazoles and their antimicrobial property evaluation from 2018 to 2024. Recent synthetic methodologies emphasize green chemistry approaches including solvent-free and catalyst-driven reactions, offering improved yields, selectivity, and environmental sustainability. Structural modifications, such as functionalization at positions 2 and 5/6 of the benzimidazole ring, were extensively investigated to enhance the antimicrobial efficacy against a broad spectrum of pathogens including multidrug-resistant bacterial and fungal strains. Furthermore, we elucidate the structure–activity relationships (SARs) of benzimidazole derivatives, enabling the rational design of highly potent antimicrobial agents. The mentioned period also witnessed the integration of hybrid molecules, wherein benzimidazoles were conjugated with other bioactive scaffolds to achieve synergistic antimicrobial effects.

In this study, two series of benzimidazole hybrids were developed and designed using different strategies. The target compounds were designed through straight chemistry pathways and were screened as possible antimicrobial agents. Twenty new compounds were synthesized, among which compounds 11 and 12 displayed excellent activity against Candida albicans and Cryptococcus neoformans with growth inhibition percentage ranging from 86.42% to 100%. For gaining better insights into the mechanistic ability of the active candidates 11 and 12, their inhibitory activity against lanosterol 14α-demethylase was studied. Results showed IC₅₀ values of 5.6 and 7.1 μM for 11 and 12, respectively, which were comparable to the reference value of fluconazole (2.3 μM), indicating low drug interaction possibilities. Notably, compound 11 displayed excellent inhibition of biofilm metabolic activity. In addition, their synergistic activity against C. neoformans displayed a 2-fold increase compared with fluconazole. Furthermore, it exhibited sustained antifungal activity with time clearance of over 24 h, which was better than the time clearance of fluconazole (6 h). Moreover, compounds 11 and 12 displayed considerable safety profiles, with no cytotoxicity reported against human embryonic kidney cells or hemolysis of red blood cells. Molecular dynamics simulation (MDS) experiments over 100 ns of compound 11 showed its ability to interact with the HEM binding site as the co-crystallized ligand (fluconazole). Finally, in silico ADMET studies predicted its significant oral bioavailability as antifungal candidates

Cancer is a highly significant medical concern, as it is the second most prevalent cause of mortality after cardiovascular diseases. It arises due to dysregulated cell cycle control, leading to a gradual decline in cellular differentiation and unrestricted cellular proliferation. Therefore, the primary objective for researchers is to develop a cancer treatment that addresses drug resistance while providing effective therapeutic benefits and minimizing side effects. Benzimidazole has garnered significant attention because it serves as an auxiliary isostere of nucleotides, which are found in several natural and biologically active molecules. Benzimidazole compounds possess a privileged pharmacophore that exhibits various pharmacological actions. Several benzimidazole derivatives exhibit dual or multiple anticancer properties through diverse mechanisms, focusing on specific compounds or employing strategies that are not gene specific. Furthermore, many drugs based on benzimidazole have previously been approved to treat cancer. This comprehensive review encompasses the most important reports on various benzimidazole hybrids, highlighting their anticancer significance, mechanism of action, and structure-activity relationships from 2005 up to 2025. These provide valuable knowledge for designing effective anticancer drugs.

Melanoma is one of the deadliest forms of cancer. The disease is incurable for many due to its aggressive, metastatic characteristics and its elevated resistance. Herein, we design and synthesize two series of target compounds oxindole-based (7a-h) and non-oxindole-based (8a-h) benzimidazole. Selected compounds were evaluated against mutant BRAFV600E and ABL2 kinases upon evaluating for anti-tumor efficacy against a preliminary 60-tumor cell line panel at NCI, USA. The NCI selected six compounds (7c, 7d, 7g, 7h, 8b, and 8h) for evaluation at five doses. Compounds 8b and 8h exhibited the highest cytotoxic potency against SK-MEL-5 with IC50 = 1.00 and 0.54 μM, respectively. Compounds 7c and 8h were the most potent to inhibit BRAFV600E with IC50 = 0.072 and 0.088 μM, respectively. While compounds 7c and 8b showed the most potent inhibitory activity against ABL2 kinases (IC50 = 0.143 and 0.236 μM, respectively). Compound 8h diminished P-glycoprotein expression by 0.2732. Molecular docking findings showed that compound 8b exhibits the highest binding affinity for the ABL2 kinase enzyme. Cytotoxicity assays in resistant melanoma cells showed IC50 values of 12.3 μM (A375) and 20.1 μM (A375-R), demonstrating potency comparable to vemurafenib. Western blot analysis showed that 8h effectively inhibited p-CrkL (Abl2 signaling) and p-ERK1/2 (BRAFV600E pathway) in A375-R melanoma cells. Compounds 8h, 7c, and 8b demonstrated the highest binding affinities for BRAFV600E. Compound 8h causes cell cycle arrest at the G1 phase, inhibiting progression to the S phase and subsequent phases (28.55 % compared to 39.02 %) and G2/M phase (13.33 % compared to 16.35 %). Furthermore, the apoptotic efficacy of 8h demonstrated a significant increase in the percentage of late apoptotic cells, reaching 13.89 % in treated cells, in contrast to 0.15 % in untreated cells. In Silico ADME profiling indicated that the proposed compounds are suitable drug candidates