Discovery of novel antituberculosis agents among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives targeting aminoacyl-tRNA synthetases

Abstract

Antibiotic resistance is a major problem of tuberculosis treatment. This provides the stimulus for the search of novel molecular targets and approaches to reduce or forestall resistance emergence in Mycobacterium tuberculosis. Earlier, we discovered a novel small-molecular inhibitor among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazoles targeting simultaneously two enzymes—mycobacterial leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS), which are promising molecular targets for antibiotic development. Unfortunately, the identified inhibitor does not reveal antibacterial activity toward M. tuberculosis. This study aims to develop novel aminoacyl-tRNA synthetase inhibitors among this chemical class with antibacterial activity toward resistant strains of M. tuberculosis. We performed molecular docking of the library of 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives and selected 41 compounds for investigation of their inhibitory activity toward MetRS and LeuRS in aminoacylation assay and antibacterial activity toward M. tuberculosis strains using microdilution assay. In vitro screening resulted in 10 compounds active against MetRS and 3 compounds active against LeuRS. Structure-related relationships (SAR) were established. The antibacterial screening revealed 4 compounds active toward M. tuberculosis mono-resistant strains in the range of concentrations 2–20 mg/L. Among these compounds, only one compound 27 has significant enzyme inhibitory activity toward mycobacterial MetRS (IC50 = 148.5 µM). The MIC for this compound toward M. tuberculosis H37Rv strain is 12.5 µM. This compound is not cytotoxic to human HEK293 and HepG2 cell lines. Therefore, 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives can be used for further chemical optimization and biological research to find non-toxic antituberculosis agents with a novel mechanism of action.

Structure‐based virtual screening and biological evaluation of novel inhibitors of mycobacterium Z‐ring formation

“…4,6 It has recently been shown that fluoroquinolones and oxaborol derivatives are quite effective in inducing mortality against these targets. 5,7,8 Another target, RNA polymerase, is involved in both initiation of DNA transcription and RNA elongation, which is one of the most important processes of cell division. 9 The cell wall of Mtb is composed of fatty acids and peptidoglycans; therefore, enzymes involved in their biosynthesis are also very attractive targets.…”

“…Thus, the most important target proteins in the cycle of replication and protein synthesis are mycobacterial DNA gyrase (topoisomerase II) 3 and aminoacyl‐tRNA synthetases, as specific targets, 4,5 especially Leucyl‐tRNA synthetase 4,6 . It has recently been shown that fluoroquinolones and oxaborol derivatives are quite effective in inducing mortality against these targets 5,7,8 . Another target, RNA polymerase, is involved in both initiation of DNA transcription and RNA elongation, which is one of the most important processes of cell division 9 .…”

Synthesis, Biological Activity, and Toxicity to Zebrafish Embryo of Benzamides Substituted with 1,2,4-Oxadiazole-Linked Pyrazole

“…Resistant pests have emerged due to adverse climate change effects, and to downsize such resistant pest varieties with new techniques is a challenging task for agronomists. , Heterocyclic compounds, including furan, pyrrole, and indole fragments, play a pivotal role in the development of novel pesticides. These compounds have gained attention in this field due to their high efficiency, diverse biological activities, environmental friendliness, and ability to accommodate various substituents. − As a bioisosteric group of amide bonds, 1,2,4-oxadiazole has demonstrated a broad spectrum of biological activities such as insecticidal properties against resistant pests − and bactericidal effects. − It also shows herbicidal activity and potential anticancer activities . Chemically belonging to the five-member nitrogenous heterocyclic skeleton with oxygen and nitrogen atoms present within its structure gives 1,2,4-oxadiazole derivatives unique characteristics that endow them with high affinity and selectivity toward target enzyme sites, consequently leading to their broad-spectrum effectiveness. − In addition, pyrazole amide derivatives have good insecticidal and fungicidal activities. , Notably, a number of pyrazole amide derivatives such as chlorantraniliprole, , tetraniliprole, thiotraniliprole, tetrachloraniliprole, dimpropyridaz, and penflufen, (Figure ), have been developed and utilized in the pesticide market.…”