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A new series of compounds combining fragments from nitazoxanide and 4-aminosalicylic acid has been synthesized and tested for their antibacterial and antimycobacterial activities. Several of the compounds showed higher potency than conventional antibiotics against different bacterial strains. Molecular docking studies were conducted to explore the possible mechanisms of action. These findings suggest the potential for designing more potent antimicrobial drugs based on substituted nitazoxanide.
A new series inspired by combining fragments from nitazoxanide (NTZ) and 4-aminosalicylic acid (4-ASA) was synthesized and screened for in vitro antibacterial and antimycobacterial activities. The majority showed higher antibacterial potency than NTZ against all the screened strains, notably, 5f, 5j, 5n and 5o with MICs 0.87-9.00 μM. Compounds 5c, 5n and 5o revealed higher potency than ciprofloxacin against K. pneumoniae, while 5i was equipotent. For E. faecalis, 3b, 5j, 5k showed higher potency than ciprofloxacin. 5j Was more potent against P. aeruginosa than ciprofloxacin, while 5n was more potent against S. aureus with MIC 0.87 μM. 5f showed equipotency to ciprofloxacin against H. pylori with MIC 1.74 μM. Compounds 3a and 3b (4-azidoNTZ, MIC 4.47 μM)) are 2 and 5-fold more potent against Mycobacterium tuberculosis (Mtb H37Rv) than NTZ (MIC 20.23 μM) and safer. 4-Azidaion and/or acetylation of NTZ improve both activities, while introducing 1,2,3-triazoles improves the antibacterial activity. Molecular docking studies within pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS) and dihydrofolate reductase (DHFR) active sites were performed to explore the possible molecular mechanisms of actions. Acceptable drug-likeness properties were found. This study may in light of further rational design of substituted NTZ as broad-spectrum more potent antimicrobial candidates.
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