Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

Autor:	Bheemanaboina RRY; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States., de Souza ML; Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United States., Gonzalez ML; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States., Mahmood SU; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States., Eck T; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States., Kreiss T; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States., Aylor SO; Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Roth A; Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Lee P; Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Pybus BS; Department of Drug Discovery, Experimental Therapeutics Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States., Colussi DJ; Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania 19140, United States., Childers WE; Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania 19140, United States., Gordon J; Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania 19140, United States., Siekierka JJ; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States., Bhanot P; Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, New Jersey 07103, United States., Rotella DP; Department of Chemistry and Biochemistry and Sokol Institute of Pharmaceutical Life Sciences, Montclair State University, Montclair, New Jersey 07043, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Nov 15; Vol. 12 (12), pp. 1962-1967. Date of Electronic Publication: 2021 Nov 15 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.1c00540
Abstrakt:	The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency. Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.)
Databáze:	MEDLINE
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