Novel 1,2,4-oxadiazole/pyrrolidine hybrids as DNA gyrase and topoisomerase IV inhibitors with potential antibacterial activity |
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Institution: | 1. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China;2. Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, PR China;3. Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia 61519, Egypt;5. Pharmacology Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia;6. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt |
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Abstract: | DNA gyrase is a promising target for antibacterial agents. Several classes of small-molecule inhibitors have been discovered in recent decades, but none of these have reached the market. We have designed a small library of 1,2,4-oxadiazole/pyrrolidine hybrids with mid nanomolar inhibitory and potent antibacterial activities against DNA gyrase and topoisomerase IV. Compounds 9, 15, 16, 19, and 21 inhibited Escherichia coli DNA gyrase to a similar extent as the reference compound, novobiocin, with inhibitory values ranging from 120 nM to 270 nM. Compound 16 was one of the most potent compounds in the series, with an IC50 value of 120 nM against E. coli gyrase, which is lower than the IC50 value of novobiocin (170 nM). Compound 16 had the highest inhibitory activity, with minimum inhibitory concentrations (MIC) of 24 and 62 ng/mL against Staphylococcus aureus and E. coli, respectively, which compared favorably with ciprofloxacin (30 and 60 ng/mL, respectively). Compounds 9, 15, 19, and 21 were similar to novobiocin in terms of their activity against E. coli and S. aureus topoisomerase IV, while compound 16 was more potent than novobiocin. |
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Keywords: | 1 2 4-Oxadiazole Gyrase Topoisomerase Pyrrolidine |
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