Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis

Abstract

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

Targeting Energy Metabolism in Mycobacterium tuberculosis , a New Paradigm in Antimycobacterial Drug Discovery

“…Thioridazine and other phenothiazines are approved antipsychotic drugs whose applicability to the treatment of TB currently is under consideration (21). The cytochrome bc 1 complex has been validated as a target of the imidazopyridines and related compounds (22–26). Imidazopyridine lead compound Q203, discovered by a phenotypic screen against M. tuberculosis in macrophages and subsequent chemical optimization (23), currently is in phase 1 clinical trials.…”

“…Diarylquinoline lead compound BDQ has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of multidrug-resistant tuberculosis. A recent high-throughput screen for inhibition of ATP synthesis in mycobacterial membrane vesicles and subsequent biochemical deconvolution identified the squaramides as a new class of ATP synthase inhibitors (26). …”

“…Hitherto, high-throughput screening efforts have mainly yielded classes of small-molecule inhibitors active on either ATP synthase (8, 26) or the cytochrome bc 1 complex (23, 25, 26). The reasons for this preference are obscure but may be related to the central role of these two enzymes in either establishing or utilizing the proton motive force.…”

“…As an example of a currently not exploited target in oxidative phosphorylation, the succinate dehydrogenase Sdh-1 has been pinpointed as a key regulator of mycobacterial oxidative phosphorylation during adaptation to low-oxygen environments (32), whereas fumarate reductase, which catalyzes the reverse reaction, was found instrumental in maintaining the proton motive force under anaerobic conditions (33). Screening using focused biochemical assays covering only part of the oxidative phosphorylation pathway (26) and/or phenotypic screening under hypoxia may be applied for discovery of new hits targeting these metabolic regulator enzymes. The cytochrome bd , an alternative terminal oxidase of the mycobacterial respiratory chain (Fig.…”

Revisión de la historia y aplicación de escuaramida en organocatálisis

“…En 2016, se reportó que tienen propiedades biológicas como antiespasmódicos e inhibidores de micobacterias (Ribeiro et al, 2016;Tantry et al, 2017), también que poseen propiedades antiinflamatorias (Busch-Petersen, 2006). En el año 2014, Olmo y colaboradores sintetizaron un derivado de escuaramida (figura 15), con resultados promisorios para el tratamiento de la enfermedad de Chagas (Olmo et al, 2014).…”