biostudies-literature00510Alsayed SSRCurtin University of TechnologyNHLBI NIH HHSNational Heart, Lung, and Blood InstituteDivision of Intramural Research, National Institute of Allergy and Infectious DiseasesAustralian Research Council7523-7540https://www.ebi.ac.uk/biostudies/studies/S-EPMC7497412biostudies-literatureUnknown10(13)Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) <i>Mycobacterium tuberculosis</i> (<i>M. tb</i>) strain. Naphthamide derivatives <b>13c</b> and <b>13d</b> were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds <b>8i</b> and <b>18b</b> had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) <i>M. tb</i> strains. It is worth noting that the two most active compounds <b>13c</b> and <b>13d</b> also exhibited the highest selective activity towards DS, MDR and XDR <i>M. tb</i> strains over mammalian cells [IC₅₀ (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.RSC advancesDesign, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents.PMC7497412DE160100482CIPRSHL133190AI27856R01 HL133190Foster NGunosewoyo HBeh CCPayne ADLuna GAlsayed SSRBishai WRLun S51falseDesign, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents.Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) <i>Mycobacterium tuberculosis</i> (<i>M. tb</i>) strain. Naphthamide derivatives <b>13c</b> and <b>13d</b> were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds <b>8i</b> and <b>18b</b> had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) <i>M. tb</i> strains. It is worth noting that the two most active compounds <b>13c</b> and <b>13d</b> also exhibited the highest selective activity towards DS, MDR and XDR <i>M. tb</i> strains over mammalian cells [IC₅₀ (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.2020-01-01T00:00:00Z2020 Feb2024-11-20T12:24:25.661Z2020-10-09T07:13:32ZS-EPMC74974123301434910.1039/c9ra10663d