Inhibitors of aminoacyl-tRNA synthetases as antimycobacterial compounds: An up-to-date review

Design and synthesis of leucylaniline derivatives as leucyl-tRNA synthetase inhibitors

“…1 H NMR (400 MHz, CDCl 3 ) d 9.88 (s, 1H, NH), 8.95 (s, 1H, NH), 7.99-7.92 (m, 2H, Ar), 7.66 (m, 1H, Ar), 7.61-7.51 (m, 3H, Ar), 7.34 (m, 1H, Ar), 6.89-6.81 (m, 1H, Ar), 3.97 (m, 1H, CH), 3.43-3.35 (m, 2H, CH 2 ), 1.75 (m, 2H, NH 2 ), 1.35 (m, 1H, CH), 0.92 (dd, J = 25.0, 6.9 Hz, 6H, CH 3 ). 13 4-((S)-2-Amino-4-methylpentanamido)-N-((tetrahydrofuran-2-yl) methyl)benzamide (8). To a solution of (S)-3-(2-Boc-amino-4methylpentanamido)-N-cyclohexyl-N-methylbenzamide (0.5 g, 0.0014 mol) in DCM, TFA (0.36 g, 0.004 mol) was added at room temperature and the mixture was stirred for 4 h. Later, it was washed with saturated NaHCO 3 solution and followed by brine solution.…”

“…Then, under the action of enzymes, Leu-AMP reacts with tRNA, transferring homologous amino acids to 2 or 3 hydroxyl groups of adenosines at the 3 0 end of the corresponding tRNA. 7,8 In 1998, Schimmel et al confirmed aaRS as an antibacterial target for the first time. 9 The inhibition of aaRS in bacteria causes the accumulation of uncharged tRNA, which induces the response of relA genes responsible for the biosynthesis of guanosine tetra-and pentapeptides.…”

Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

“…Bedaquiline was approved by the US Food and Drug Administration (FDA) in 2012, delamanid was accredited by the European Medicines Agency in 2014 and pretomanid was developed by the Global Alliance in 2019 6 , 7 . Many new drugs are in the stage of clinical trials, lead compounds with many targets are in a lead-optimization state, such as InhA inhibitors 8 , PKS13 inhibitors 9 , MmpL3 inhibitors 10 , DprE1 inhibitors 11 , DNA gyrase inhibitors 12 , RNA polymerase inhibitors 13 , and LeuRS inhibitors 14 . Three compounds are in preclinical development, such as CPZEN-45 15 , DC-159a 16 , and SQ609 17 .…”

Docking-Based Virtual Screening for the Discovery of 1,3,4-Oxadiazoles as Aminoacyl-tRNA Synthetase Inhibitors

“…A total of 23 aaRSs have been described with methionyl-tRNA synthetase (MetRS) being one of the most studied enzymes since it recognizes an initiator tRNA as well as the tRNA delivering methionine for elongation of the protein chain. Due to the pivotal role that MetRS plays in protein synthesis, this enzyme has been described as a validated drug target in many disease-relevant organisms (Bouz & Zitko, 2021;Buckner et al, 2019;Torrie et al, 2017;Ojo et al, 2016;Hussain et al, 2015). In particular, MetRS has been successfully exploited as a target in Gram-positive bacteria with MetRS inhibitor CRS3123 having recently completed two-phase I clinical trials for the treatment of Clostridium difficile infections (Lomeli et al, 2019;Nayak et al, 2017).…”