3 research outputs found
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Whole-cell high-throughput
screening of the AstraZeneca compound
library against the asexual blood stage of Plasmodium
falciparum (<i>Pf</i>) led to the identification
of amino imidazoles, a robust starting point for initiating a hit-to-lead
medicinal chemistry effort. Structure–activity relationship
studies followed by pharmacokinetics optimization resulted in the
identification of <b>23</b> as an attractive lead with good
oral bioavailability. Compound <b>23</b> was found to be efficacious
(ED<sub>90</sub> of 28.6 mg·kg<sup>–1</sup>) in the humanized P. falciparum mouse model of malaria (<i>Pf</i>/SCID model). Representative compounds displayed a moderate to fast
killing profile that is comparable to that of chloroquine. This series
demonstrates no cross-resistance against a panel of <i>Pf</i> strains with mutations to known antimalarial drugs, thereby suggesting
a novel mechanism of action for this chemical class
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 imidazo[1,2-<i>a</i>]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
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 imidazo[1,2-<i>a</i>]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