title: Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: pharmacophore mapping from known antibacterial leads.
abstract: Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
authors.forename: Karyakulam Andrews
authors.initials: KA
authors.lastname: Bobesh
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
authors.forename: Janupally
authors.initials: J
authors.lastname: Renuka
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, 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, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
authors.forename: Singh Kakan
authors.initials: SK
authors.lastname: Shruti
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, 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, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, Jawaharnagar, RangaReddy District, Hyderabad 500 078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009584:Nitrogen / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D010880:Piperidines; D059005:Topoisomerase II Inhibitors; C032727:piperidine; D027081:DNA Gyrase; D009584:Nitrogen
keywords: Aminopiperidine; Antimycobacterial; Cytotoxicity; DNA gyrase; Supercoiling; Tuberculosis