Design, synthesis, and antibacterial activity of a new series of ciprofloxacin-thiadiazole hybrid

Abstract

This study synthesized novel ciprofloxacin analogs bearing the 2-amino-1,3,4-thiadiazole ring, including tryptophan and different sulfonamides, to act as antimicrobial agents. Then, the activities of the synthesized hybrids were screened against 18 tested bacterial isolates from 4 standard strains (Escherichia coli ATCC 8739, Staphylococcus aureus ATCC 25,923, Acinetobacter baumannii ATCC 19,606, and Pseudomonas aeruginosa PAO1) and 14 clinical strains (2 Enterobacter cloacae and 12 Klebsiella pneumonia isolates). Investigations revealed that compound 2 showed better antimicrobial activities among the synthesized compounds than the standard drug, ciprofloxacin, demonstrated by its lower MIC and MBC values. We also notably observed that compared to ciprofloxacin, compound 2 maintained its activity for a longer time without inducing resistance in the tested bacterium. Hence, we conducted a time-to-kill assay and compared the results with its parent drug, followed by a molecular modeling simulation study through the docking of compound 2 into E. coli DNA gyrase enzyme active site to elucidate its binding modes to the receptor. Then, we compared these results with ciprofloxacin and calculated the physicochemical descriptors, ADME parameters, pharmacokinetic properties, and drug-like nature profile of compound 2 as the most potent were also calculated. Based on our findings, we conclude that with further modifications of compound 2, the design of a new and optimized fluoroquinolone generation should be possible.