Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2-Quinolin-4-yloxyacetamides

Abstract

In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound 83 which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program.

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

“…To date, these chemical starting points have led to the discovery of two new classes of QcrB inhibitors, the 2-quinolin-4-yloxyacetamides (QOA) and the arylvinylpiperazine amides. Several SAR studies of the QOAs have been reported and are in agreement regarding the potency of this chemical entity against M. tb, the lack of toxicity in a zebrafish model and the narrow-spectrum activity specific for M. tb [132,154,155]. Independent work through cross-resistance studies and isolation of resistance mutants harbouring the mutation T313A in QcrB confirmed cytochrome bcc as the target of QOAs [155,156].…”

“…Independent work through cross-resistance studies and isolation of resistance mutants harbouring the mutation T313A in QcrB confirmed cytochrome bcc as the target of QOAs [155,156]. The solubility and stability of this series, as well as their in vivo potency, remain to be addressed [133,154]. The arylvinylpiperazine amides were generated through lead optimisation and SAR studies conducted with GW861072X from the GSK screen, which was an attractive starting point for its structural simplicity and potent activity against M. bovis and M. tb [76].…”

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Furthermore, they deduced that the amide bond was responsible for the observed metabolic lability. Further optimisation led to the development of a benzoxazole analogue ( 359 ), which possessed vastly improved metabolic stability and decreased hERG affinity, albeit with reduced M. tuberculosis inhibitory activity …”

SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc1 inhibitors

“…During the preparation of this manuscript, two groups have reported the results of their studies of the QOA class, confirming compound potency, selectivity for M. tuberculosis and lack of toxicity in a Danio rerio (zebrafish) model. 14 Herein we report our efforts in optimizing the in vitro anti-tuberculosis activity of the more potent GSK QOA analogue 5 and also identify, via use of selective mutant strains, their cellular target as involving the cytochrome bc 1 complex.…”