title: Benzothiazinone-piperazine derivatives as efficient Mycobacterium tuberculosis DNA gyrase inhibitors.
abstract: OBJECTIVE
  Bacterial DNA topoisomerases are unique in maintaining the DNA topology for cell viability. Mycobacterium tuberculosis (MTB) DNA gyrase, a sole type II topoisomerase has a larger scope as a target for developing novel therapeutics. In this study, an effort was made towards the design and synthesis of benzothiazinone-piperazine hybrid analogues to obtain the possibility of it to lead development through the molecular hybridization technique.
  
  
  METHODS
  A five-step scheme was followed to obtain a series of 36 benzothiazinone-piperazine derivatives and to evaluate them for MTB DNA gyrase inhibition, antimycobacterial and cytotoxicity studies.
  
  
  RESULTS
  Compound N-(4-chlorophenyl)-4-(6-nitro-4-oxo-4H-benzo[e][1,3]thiazin-2-yl)piperazine-1-carbothioamide (18) showed greater inhibitory potential with an IC50 of 0.51 ± 0.16 μM in the DNA supercoiling assay of MTB with a moderate anti-tubercular activity of 4.41 μM. The compound even passed the safety profile of eukaryotic cell cytotoxicity with a 1.81% inhibition in the RAW 264.7 cell line at 100 μM concentration.
  
  
  CONCLUSIONS
  This study describes the discovery of benzothiazinone as gyrase inhibitors with potent MTB MIC and inhibitory profiles of the gyrase enzyme with less cytotoxic effect. Furthermore, it is believed that this class of compounds has the potential to be further developed as an anti-TB drug candidate.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Chandran
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
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: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Pedgaonkar
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors.forename: Vanaparthi
authors.initials: V
authors.lastname: Asmitha
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: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000494:pharmacology*; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001581:Benzothiadiazines; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; D000077489:Piperazine; D027081:DNA Gyrase
keywords: DNA gyrase; Minimum inhibitory concentration; Supercoiling; Tuberculosis