Journal article
3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance
ACS infectious diseases, v 10(7)
11 Jun 2024
PMID: 38862127
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- 3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance
- Creators
- Sovitj Pou - VA Portland Health Care SystemRolf W. Winter - VA Portland Healthcare Syst, Portland, OR 97239 USARozalia A. Dodean - VA Portland Health Care SystemKatherine Liebman - VA Portland Health Care SystemYuexin Li - VA Portland Health Care SystemMichael W. Mather (Corresponding Author) - Drexel UniversityBinod Nepal (Corresponding Author) - Drexel UniversityAaron Nilsen - VA Portland Health Care SystemMason J. Handford - Oregon Health & Science UniversityTeresa M. Riscoe (Corresponding Author) - Oregon Health & Science UniversitySydney Laxson - VA Portland Health Care SystemPayton J. Kirtley - Oregon Health & Science UniversityMaya Aleshnick - Oregon Health & Science UniversityLev N. Zakharov - Ctr Adv Mat Characterizat Oregon CAMCOR, Eugene, OR 97403 USAJane X. Kelly - VA Portland Health Care SystemMartin J. Smilkstein - VA Portland Health Care SystemBrandon K. Wilder - Oregon Health & Science UniversitySandhya Kortagere - Drexel UniversityAkhil B. Vaidya - Drexel UniversityP. Holland Alday - VA Portland Health Care SystemJ. Stone Doggett - VA Portland Health Care SystemMichael K. Riscoe - VA Portland Health Care System
- Publication Details
- ACS infectious diseases, v 10(7)
- Publisher
- Amer Chemical Soc
- Number of pages
- 24
- Grant note
- R01AI100569; R01AI141412 / VA Research Career Scientist Award PR181134; BX002440 / US National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 AI154499; SCR 019048 / National Science Foundation; National Science Foundation (NSF) NIH/NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) i01 BX003312 / U.S. Department of Defense; United States Department of Defense IK2BX0940 / VA Merit Review Award; US Department of Veterans Affairs 14S-RCS001 / United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Program Award; US Department of Veterans Affairs MRI 1828573 / US Department of Veterans Affairs Biomedical Laboratory Research Program; US Department of Veterans Affairs BX004522 / U.S. Department of Defense Peer Reviewed Medical Research Program; United States Department of Defense
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:001247152000001
- Scopus ID
- 2-s2.0-85196121445
- Other Identifier
- 991021889608504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Infectious Diseases