AI Article Synopsis
- - Malaria is still a major global health threat, necessitating new drugs to help eradicate it.
- - Researchers have developed a new type of antimalarial drug, an acridone chemotype, that effectively targets both liver and blood stages of malaria parasites.
- - Tested compounds showed promising results, including strong inhibition of resistant malaria strains, effectiveness in animal models, and potential for liver-stage infection prevention.
Article Abstract
Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822569 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.8b01961 | DOI Listing |
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