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    Design and synthesis of new HCV NS3/4A protease inhibitors to effective against drug resistance
    (Elsevier, 2025) Oksuz, Zehra; Aktekin, Mine Buga; Alagoz, Mehmet Abdullah; Kuzucu, Mehmet; Serin, Mehmet Sami; Algul, Oztekin
    HCV NS3/4A protease is a crucial target for antiviral therapy, but resistance remains a significant challenge. Understanding substrate recognition is key to developing effective inhibitors. The aim of this study was to investigate four new compounds (10-12 and 13) that mimic natural substrate binding. Compound activities were determined with enzymatic assays and anti-proliferative activities were evaluated. Compound 12 exhibited the highest potency with an IC50 of 17.78 mu M and a Ki value of 16.39 mu M. All compounds demonstrated moderate to high anti-proliferative activity against HFF-1 and HepG2 cells, with 12 and 11 showing the most potent effects. In silico studies revealed that compounds 11 and 12 formed stable complexes with the HCV NS3/4A protease, establishing significant interactions with key residues of the catalytic triad. Their docking scores and molecular dynamics simulations were comparable to those of the reference molecule, simeprevir. These findings suggest that compounds 10-12 and 13 hold promise as potential therapeutic agents against HCV, warranting further investigation.
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    Exploring bisbenzimidazole-chalcone hybrid compounds: Dual-action as antibacterial agents targeting biofilm formation and E. coli DNA gyrase inhibition
    (Elsevier, 2025) Adal, Ercan; Oksuz, Zehra; Ozkul, Ceren; Nigiz, Seyma; Alagoz, M. Abdulah; Dogen, Aylin; Simsek, Rahime
    The emergence of antibiotic-resistant pathogens has reduced the efficacy of current antimicrobial therapies, emphasizing the need for new therapeutic agents. This study presents the design, synthesis, and evaluation of bisbenzimidazole-chalcone hybrid compounds as potential antimicrobial agents. These compounds were tested for their antimicrobial activity against eleven common pathogens, as well as their ability to inhibit biofilm formation and eradicate preformed biofilms in Escherichia coli. Compounds EA1, EA3, EA4, and EA5 demonstrated antibacterial activity against E. coli comparable to ampicillin (31.25 mu g/mL) and outperformed the other tested compounds. Notably, EA4 and EA5 inhibited biofilm formation at sub-MIC concentrations and effectively eradicated preformed biofilms, as confirmed by the crystal violet assay. The synergistic effects of the most active compounds in combination with ampicillin were assessed using checkerboard synergy testing, with all combinations showing 'indifference' effects. Further analysis of the most potent compounds against E. coli ATCC 25,922 included the inhibition of DNA gyrase using E. coli DNA gyrase and a plasmid-based relaxed DNA kit. Molecular docking and molecular dynamics simulations were conducted to elucidate the binding modes and stability of these compounds within E. coli DNA gyrase enzymes. EA4 exhibited significant affinity for DNA gyrase B subunit (docking score: -4.026 kcal/mol, average RMSD value: 4.4 & Aring;), while EA5 displayed dual affinity for both DNA gyrase B subunit and DNA gyrase A subunit (docking scores: -6.944 and -3.432 kcal/mol, respectively), maintaining stable interactions in the active sites during simulations (average RMSD values of 3.2 & Aring; and 3.1 & Aring;). These results highlight the potential of bisbenzimidazole-chalcone hybrids as promising antibacterial agents, particularly in their dualtargeting capabilities against biofilm formation and DNA gyrase inhibition.