title: Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors.
abstract: Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue 27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15 μM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Sonali
authors.initials: S
authors.lastname: Kotagiri
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Renuka
authors.initials: R
authors.lastname: Janupally
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Suryadevara
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Jonnalagadda Padma
authors.initials: JP
authors.lastname: Sridevi
authors.affiliation: Dr Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Zephase Therapeutics (An Incubated Company at the Dr Reddy's Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
authors.forename: Raghavender
authors.initials: R
authors.lastname: Medishetti
authors.affiliation: Dr Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India; Zephase Therapeutics (An Incubated Company at the Dr Reddy's Institute of Life Sciences), University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D000995:Antitubercular Agents; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D000251:Adenosine Triphosphatases; D027081:DNA Gyrase
keywords: Gyrase ATPase domain; Medium throughput screening; Mycobacterium tuberculosis; Tuberculosis; hERG