title: 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation.
abstract: Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of antitubercular drug discovery. In the present study, we employed structural optimization of the reported GyrB inhibitor resulting in synthesis of a series of 46 novel quinoline derivatives. The compounds were evaluated for their in vitro Mycobacterium smegmatis GyrB inhibitory ability and Mycobacterium tuberculosis DNA supercoiling inhibitory activity. The antitubercular activity of these compounds was tested over Mtb H37Rv strain and their safety profile was checked against mouse macrophage RAW 264.7 cell line. Among all, three compounds (23, 28, and 53) emerged to be active displaying IC₅₀ values below 1 μM against Msm GyrB and were found to be non-cytotoxic at 50 μM concentration. Compound 53 was identified to be potent GyrB inhibitor with 0.86 ± 0.16 μM and an MIC (minimum inhibitory concentration) of 3.3 μM. The binding affinity of this compound towards GyrB protein was analysed by differential scanning fluorimetry which resulted in a positive shift of 3.3 °C in melting temperature (Tm) when compared to the native protein thereby reacertaining the stabilization effect of the compound over protein.
authors: Department of Pharmacy, Birla Institute of Technology &Science Pilani Hyderabad Campus, Hyderabad 500078, India.
authors: Brahmam
authors: B
authors: Medapi
authors: Department of Pharmacy, Birla Institute of Technology &Science Pilani Hyderabad Campus, Hyderabad 500078, India.
authors: Priyanka
authors: P
authors: Suryadevara
authors: Department of Pharmacy, Birla Institute of Technology &Science Pilani Hyderabad Campus, Hyderabad 500078, India.
authors: Janupally
authors: J
authors: Renuka
authors: Department of Pharmacy, Birla Institute of Technology &Science Pilani Hyderabad Campus, Hyderabad 500078, India.
authors: Jonnalagadda Padma
authors: JP
authors: Sridevi
authors: Department of Pharmacy, Birla Institute of Technology &Science Pilani Hyderabad Campus, Hyderabad 500078, India.
authors: Perumal
authors: P
authors: Yogeeswari
authors: Department of Pharmacy, Birla Institute of Technology &Science Pilani Hyderabad Campus, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.
authors: Dharmarajan
authors: D
authors: Sriram
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D000995:Antitubercular Agents; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; C001920:4-aminoquinoline
keywords: Cytotoxicity; DNA gyrase B; DNA supercoil assay; Differential scanning fluorimetry; Mycobacterium tuberculosis