Optimization of diastereomeric dihydropyridines as antimalarials.

Autor: Van Horn KS; Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States. Electronic address: k.vanhorn@neu.edu., Zhao Y; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States., Parvatkar PT; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States., Maier J; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States., Mutka T; Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL, 33612, United States., Lacrue A; Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL, 33612, United States., Brockmeier F; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States., Ebert D; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, United States., Wu W; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, United States., Casandra DR; Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL, 33612, United States., Namelikonda N; Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States., Yacoub J; Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States., Sigal M; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States., Knapp S; Department of Chemistry and Chemical Biology, Rutgers - The State University of New Jersey, 610 Taylor Road, Piscataway, NJ, 08854, United States., Floyd D; Department of Chemistry and Chemical Biology, Rutgers - The State University of New Jersey, 610 Taylor Road, Piscataway, NJ, 08854, United States., Waterson D; Medicines for Malaria Venture, 20, Route de Pré-Bois, P.O. Box 1826, 1215, Geneva, 15, Switzerland., Burrows JN; Medicines for Malaria Venture, 20, Route de Pré-Bois, P.O. Box 1826, 1215, Geneva, 15, Switzerland., Duffy J; Medicines for Malaria Venture, 20, Route de Pré-Bois, P.O. Box 1826, 1215, Geneva, 15, Switzerland., DeRisi JL; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, 94158, United States; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, United States., Kyle DE; Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Boulevard, Tampa, FL, 33612, United States; Center for Tropical & Emerging Global Diseases, University of Georgia, Athens, GA, 30602, United States., Guy RK; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40506, United States., Manetsch R; Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, Tampa, FL, 33620, United States; Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States; Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA, 02115, United States. Electronic address: r.manetsch@northeastern.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116599. Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1016/j.ejmech.2024.116599
Abstrakt: The increase in research funding for the development of antimalarials since 2000 has led to a surge of new chemotypes with potent antimalarial activity. High-throughput screens have delivered several thousand new active compounds in several hundred series, including the 4,7-diphenyl-1,4,5,6,7,8-hexahydroquinolines, hereafter termed dihydropyridines (DHPs). We optimized the DHPs for antimalarial activity. Structure-activity relationship studies focusing on the 2-, 3-, 4-, 6-, and 7-positions of the DHP core led to the identification of compounds potent (EC 50  < 10 nM) against all strains of P. falciparum tested, including the drug-resistant parasite strains K1, W2, and TM90-C2B. Evaluation of efficacy of several compounds in vivo identified two compounds that reduced parasitemia by >75 % in mice 6 days post-exposure following a single 50 mg/kg oral dose. Resistance acquisition experiments with a selected dihydropyridine led to the identification of a single mutation conveying resistance in the gene encoding for Plasmodium falciparum multi-drug resistance protein 1 (PfMDR1). The same dihydropyridine possessed transmission blocking activity. The DHPs have the potential for the development of novel antimalarial drug candidates.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.
(Copyright © 2024. Published by Elsevier Masson SAS.)
Databáze: MEDLINE
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