4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation

European Journal of Medicinal Chemistry
Brahmam MedapiDharmarajan Sriram

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.

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Citations

Aug 16, 2016·European Journal of Medicinal Chemistry·Jun-Jie KohShouping Liu
Aug 30, 2016·European Journal of Medicinal Chemistry·Kavita ChaudhariHarun M Patel
Dec 1, 2017·Frontiers in Molecular Biosciences·Michael A ReicheValerie Mizrahi
Mar 6, 2019·Current Topics in Medicinal Chemistry·Swetarka DasSidharth Chopra
Aug 15, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Mohammad M Al-SaneaClaudiu T Supuran
Nov 17, 2020·European Journal of Medicinal Chemistry·Pankaj S GiraseRajshekhar Karpoormath
May 26, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Andrés-Felipe Villamizar-MogotocoroVladimir V Kouznetsov

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