5 research outputs found
Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure-activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-beta-D-ribose 2 '-oxidase
We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-beta-D-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too. (c) 2015 Elsevier Ltd. All rights reserved
Whole cell screen based identification of spiropiperidines with potent antitubercular properties
Whole cell screen based identification of spiropiperidines with potent antitubercular properties
Discovery of Imidazo[1,2‑<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
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 imidazoÂ[1,2-<i>a</i>]Âpyridine 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
Discovery of Imidazo[1,2‑<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
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 imidazoÂ[1,2-<i>a</i>]Âpyridine 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