bedaquiline and quinoline

Towards a quest for establishing new antitubercular agents, we have designed new quinoline-triazole hybrid analogs in a six-step reaction sequence involving versatile reactions like Vilsmeier-Haack and click reaction protocol. The design is based on the structural modification of bedaquiline moiety and involves molecular hybridization approach. The structure of the synthesized product was elucidated by single crystal X-ray diffraction study. The synthesized target compounds were screened for their antitubercular activity against Mycobacterium bovis. Interestingly, two compounds of the series (8d and 8m) showed significant inhibition with MIC of 31.5 and 34.8 μM. Compounds bearing 3-fluoro phenyl and n-octyl groups on the 1,2,3-triazole ring emerged as the most potent leads among the compounds tested. Further these hit compounds were also screened for their cytotoxic effect on human embryonic kindey 293 (HEK293) cells and other cancer cell lines such as HeLa (Cervical), PC3 (Prostate), Panc-1 (Pancreatic) and SKOV3 (Ovarian) indicating to be safer with the minimal cytotoxicity.

Topics: Antitubercular Agents; Cell Line, Tumor; Cell Survival; Click Chemistry; Crystallization; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Quinolines; Structure-Activity Relationship; Triazoles

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC

Topics: Antitubercular Agents; Diarylquinolines; Drug Design; Drug Resistance, Multiple, Bacterial; Mycobacterium tuberculosis; Quinolines; Structure-Activity Relationship

A series of novel quinoline-oxadiazole hybrid compounds was designed based on stepwise rational modification of the lead molecules reported previously, in order to enhance bioactivity and improve druglikeness. The hybrid compounds synthesized were screened for biological activity against Mycobacterium tuberculosis H37Rv and for cytotoxicity in HepG2 cell line. Several of the hits exhibited good to excellent anti-tuberculosis activity and selectivity, especially compounds 12m, 12o and 12p, showed minimum inhibitory concentration values<0.5μM and selectivity index>500. The results of this study open up a promising avenue that may lead to the discovery of a new class of anti-tuberculosis agents.

Topics: Animals; Antitubercular Agents; Cell Survival; Hep G2 Cells; Humans; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Oxadiazoles; Quinolines; Rats; Structure-Activity Relationship; Tuberculosis