title: Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors.
abstract: Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC₅₀ of 0.95 ± 0.12 μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC₅₀ of 0.62 ± 0.16 μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG).
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors: Brahmam
authors: B
authors: Medapi
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors: Janupally
authors: J
authors: Renuka
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors: Shalini
authors: S
authors: Saxena
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors: Jonnalagadda Padma
authors: JP
authors: Sridevi
authors: 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: Raghavender
authors: R
authors: Medishetti
authors: 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: Pushkar
authors: P
authors: Kulkarni
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India.
authors: Perumal
authors: P
authors: Yogeeswari
authors: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, R.R. District, Hyderabad 500078, Andhra Pradesh, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors: Dharmarajan
authors: D
authors: Sriram
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D000900:Anti-Bacterial Agents; D010880:Piperidines; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C037219:quinoline; D027081:DNA Gyrase
keywords: Aminopiperidine; DNA gyrase; Quinoline; Tuberculosis