3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance.

Autor:	Pou S; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Winter RW; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Dodean RA; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Liebman K; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Li Y; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Mather MW; Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, United States., Nepal B; Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, United States., Nilsen A; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States.; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States., Handford MJ; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States., Riscoe TM; Department of Microbiology and Molecular Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States., Laxson S; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Kirtley PJ; Vaccine & Gene Therapy Institute (VGTI), Oregon Health and Science University (West Campus), 505 NW 185th Avenue, #1, Beaverton, Oregon 97006, United States., Aleshnick M; Vaccine & Gene Therapy Institute (VGTI), Oregon Health and Science University (West Campus), 505 NW 185th Avenue, #1, Beaverton, Oregon 97006, United States., Zakharov LN; Center for Advanced Materials Characterization in Oregon (CAMCOR), 1443 E. 13th Avenue, Eugene, Oregon 97403, United States., Kelly JX; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Smilkstein MJ; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States., Wilder BK; Vaccine & Gene Therapy Institute (VGTI), Oregon Health and Science University (West Campus), 505 NW 185th Avenue, #1, Beaverton, Oregon 97006, United States., Kortagere S; Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, United States., Vaidya AB; Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, United States., Alday PH; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States.; School of Medicine Division of Infectious Diseases, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States., Doggett JS; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States.; School of Medicine Division of Infectious Diseases, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States., Riscoe MK; VA Portland Healthcare System, 3710 SW US Veterans Hospital Road, Portland, Oregon 97239, United States.; Department of Microbiology and Molecular Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2024 Jul 12; Vol. 10 (7), pp. 2419-2442. Date of Electronic Publication: 2024 Jun 11.
DOI:	10.1021/acsinfecdis.4c00140
Abstrakt:	ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331 , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596 , a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598 , a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.
Databáze:	MEDLINE
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