Arylquinolinecarboxamides: Synthesis,in vitro and in silico studies against Mycobacterium tuberculosis |
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Authors: | Fostino R. B. Bokosi Richard M. Beteck Audrey Jordaan Ronnet Seldon Digby F. Warner Tendamudzimu Tshiwawa Kevin Lobb Setshaba D. Khanye |
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Affiliation: | 1. Department of Chemistry, Faculty of Science, Rhodes University, Makhanda, South Africa;2. SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa;3. SAMRC Drug Discovery and Development Unit, University of Cape Town, Cape Town, South Africa |
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Abstract: | A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines in five simple and convenient synthetic steps. The structures of all new products were confirmed by routine spectroscopic methods: IR, 1H and 13C NMR, and HRMS (electrospray ionization). The resulting arylquinolinecarboxamides were subjected to biological screening assay for in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modest antitubercular activity with compounds 8–11 , 15 and 19 exhibiting MIC90 values in the range of 32–85 μM. The antitubercular data suggested that inhibition of Mtb can be imparted by the introduction of a non-polar substituent on C-6 of the quinoline scaffold. Further, to understand the possible mode of action of the series, the reported compounds and bedaquiline were subjected to in silico docking studies against MtbATPase to determine their potential to interfere with the mycobacterial adenosine triphosphate (ATP) synthase. The results showed that these compounds have the potential to serve as antimycobacterial agents. In silico ADME pharmacokinetic prediction results showed the ability of these arylquinolinecarcboxamides to be absorbed, distributed, metabolized and excreted efficiently. |
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Keywords: | antitubercular arylquinolinecarboxamides MtbATPase Mycobacterium tuberculosis |
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