Design and Biological Evaluation of Furan/Pyrrole/Thiophene‐2‐carboxamide Derivatives as Efficient DNA GyraseB Inhibitors of Staphylococcus aureus. (19th February 2015)

• Record Type: Journal Article
• Authors: Janupally, Renuka; Medepi, Bhramam; Brindha Devi, Parthiban; Suryadevara, Priyanka; Jeankumar, Variam Ullas; Kulkarni, Pushkar; Yogeeswari, Perumal; Sriram, Dharmarajan
• Is Part Of: Chemical biology & drug design. Volume 86:Number 4(2015:Oct.)
• Page Start: 918
• Page End: 925
• Publication Date: 2015-02-19
• Subjects: Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12529
• Languages: English
• ISSNs: 1747-0277

Abstract

<abstract abstract-type="main" id="cbdd12529-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>μ</italic><sc>m</sc>. Subsequently, analogues of this lead were developed and evaluated through <italic>in vitro</italic> assays and <italic>in vivo</italic> studies. Among the 24 analogues, compound <bold>22</bold> was found to be the top hit with an improved DNA gyraseB activity of 5.35 ± 0.61 <italic>μ</italic><sc>m</sc>, 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.</p> </abstract>