Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as Efficient DNA GyraseB Inhibitors of Staphylococcus aureus |
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| Authors: | Renuka Janupally Bhramam Medepi Parthiban Brindha Devi Priyanka Suryadevara Variam Ullas Jeankumar Pushkar Kulkarni Perumal Yogeeswari Dharmarajan Sriram |
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| Affiliation: | 1. Department of Pharmacy, Birla Institute of Technology & Science‐Pilani, Hyderabad, Andhra Pradesh, India;2. Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Andhra Pradesh, India;3. Zephase Therapeutics (An Incubated Company at the Dr. Reddy's Institute of Life Sciences), University of Hyderabad Campus, Hyderabad, Andhra Pradesh, India |
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| Abstract: | DNA topoisomerases are well‐validated targets in micro‐organisms. DNA gyraseB is one of the most important enzymes among them as per their clinical importance. In earlier study, a novel lead 4‐((4‐(furan‐2‐carboxamido)phenyl)amino)‐4‐oxobutanoic acid was identified as inhibitor against DNA gyraseB with an IC50 of 12.88 ± 1.39 μm . Subsequently, analogues of this lead were developed and evaluated through in vitro assays and in vivo studies. Among the 24 analogues, compound 22 was found to be the top hit with an improved DNA gyraseB activity of 5.35 ± 0.61 μm , and the binding affinity of this compound was further ascertained biophysically through differential scanning fluorimetry. The most potent ligand did not show any signs of cardiotoxicity in zebra fish ether‐ago‐go‐related gene, ascertaining the safety profile of this series a breakthrough among the previously reported cardiotoxic gyraseB inhibitors. |
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| Keywords: | biofilm cytotoxicity DNA gyrase
Staphylococcus aureus
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