title: Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain.
abstract: DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis (Mtb), unlike other bacteria and its absence in human being makes it a clinically validated target for developing anti-tubercular leads against Mtb. In the present study, our effort was to optimize and synthesize a series of compounds by a combination of molecular docking, and synthetic chemistry approach for better activity. A series of twenty eight substituted 2-amino-5-phenylthiophene-3-carboxamide derivatives were designed based on our earlier reported Mtb GyrB inhibitor lead. Hit expansion of the previously identified lead by chemical synthesis led to improved inhibitor with an IC50 value of 0.86±0.81μM against Mtb DNA gyrase supercoiling and Mycobacterium smegmatis GyrB IC50 of 1.35±0.58μM. Further a biophysical investigation using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain.
authors.affiliation: Centre for Infectious Disease Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Centre for Infectious Disease Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Samala
authors.affiliation: Centre for Infectious Disease Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
authors.affiliation: Centre for Infectious Disease Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
authors.forename: Jonnalagadda Padma
authors.initials: JP
authors.lastname: Sridevi
authors.affiliation: Centre for Infectious Disease Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Centre for Infectious Disease Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D000995:Antitubercular Agents; D027081:DNA Gyrase
keywords: Antimycobacterial; Cytotoxicity; DNA gyrase; Tuberculosis