Sovitj Pou, Rolf W. Winter, Rozalia A. Dodean, Katherine Liebman, Yuexin Li, Michael W. Mather, Binod Nepal, Aaron Nilsen, Mason J. Handford, Teresa M. Riscoe, Sydney Laxson, Payton J. Kirtley, Maya Aleshnick, Lev N. Zakharov, Jane X. Kelly, Martin J. Smilkstein, Brandon K. Wilder, Sandhya Kortagere*, Akhil B. Vaidya*, P. Holland Alday, J. Stone Doggett and Michael K. Riscoe*,
{"title":"3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance","authors":"Sovitj Pou, Rolf W. Winter, Rozalia A. Dodean, Katherine Liebman, Yuexin Li, Michael W. Mather, Binod Nepal, Aaron Nilsen, Mason J. Handford, Teresa M. Riscoe, Sydney Laxson, Payton J. Kirtley, Maya Aleshnick, Lev N. Zakharov, Jane X. Kelly, Martin J. Smilkstein, Brandon K. Wilder, Sandhya Kortagere*, Akhil B. Vaidya*, P. Holland Alday, J. Stone Doggett and Michael K. Riscoe*, ","doi":"10.1021/acsinfecdis.4c00140","DOIUrl":null,"url":null,"abstract":"<p >ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, <b>ELQ-331</b>, 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 <b>ELQ-596</b>, a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant <i>Plasmodium falciparum</i> parasites. <b>ELQ-598</b>, a prodrug of <b>ELQ-596</b> with diminished crystallinity, is more effective vs murine malaria than its progenitor <b>ELQ-331</b> 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, <b>ELQ-596</b> 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.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsinfecdis.4c00140","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.