Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4- b ]pyridines.

Autor:	Eagon S; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Hammill JT; Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40508, United States., Sigal M; Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Ahn KJ; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Tryhorn JE; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Koch G; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States., Belanger B; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Chaplan CA; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Loop L; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Kashtanova AS; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Yniguez K; SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025, United States., Lazaro H; Promega Biosciences, 277 Granada Drive, San Luis Obispo, California 93401, United States., Wilkinson SP; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Rice AL; Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40508, United States., Falade MO; Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40508, United States., Takahashi R; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Kim K; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Cheung A; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., DiBernardo C; Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, United States., Kimball JJ; Promega Biosciences, 277 Granada Drive, San Luis Obispo, California 93401, United States., Winzeler EA; School of Medicine, University of California San Diego, La Jolla, California 92093, United States., Eribez K; School of Medicine, University of California San Diego, La Jolla, California 92093, United States., Mittal N; School of Medicine, University of California San Diego, La Jolla, California 92093, United States., Gamo FJ; GlaxoSmithKline, Global Health, DDW, Tres Cantos, Madrid 28760, Spain., Crespo B; GlaxoSmithKline, Global Health, DDW, Tres Cantos, Madrid 28760, Spain., Churchyard A; Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom., García-Barbazán I; Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom., Baum J; Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom., Anderson MO; Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California 94132, United States., Laleu B; Medicines for Malaria Venture (MMV), P.O. Box 1826, 20, Route de Pré-Bois, Geneva 1215, Switzerland., Guy RK; Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40508, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Oct 22; Vol. 63 (20), pp. 11902-11919. Date of Electronic Publication: 2020 Oct 01.
DOI:	10.1021/acs.jmedchem.0c01152
Abstrakt:	Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo[3,4- b ]pyridines targeting Plasmodium falciparum , the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Q o binding site of cytochrome bc 1 .
Databáze:	MEDLINE
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