Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-02-12 DOI:10.1021/acsinfecdis.4c00666

Andrew Spaulding, Amrita Sharma, Miriam A Giardini, Benjamin Hoffman, Jean A Bernatchez, Laura-Isobel McCall, Claudia M Calvet, Jasmin Ackermann, Julia M Souza, Diane Thomas, Caroline C Millard, William G Devine, Baljinder Singh, Everton M Silva, Susan E Leed, Norma E Roncal, Erica C Penn, Jessey Erath, Gaurav Kumar, Yadira Sepulveda, Arnold Garcia, Ana Rodriguez, Nelly El-Sakkary, Richard J Sciotti, Robert F Campbell, Jeremiah D Momper, James H McKerrow, Conor R Caffrey, Jair L Siqueira-Neto, Michael P Pollastri, Kojo Mensa-Wilmot, Lori Ferrins

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引用次数: 0

Abstract

Neglected tropical diseases such as Chagas disease, human African trypanosomiasis, leishmaniasis, and schistosomiasis have a significant global health impact in predominantly developing countries, although these diseases are spreading due to increased international travel and population migration. Drug repurposing with a focus on increasing antiparasitic potency and drug-like properties is a cost-effective and efficient route to the development of new therapies. Here we identify compounds that have potent activity against Trypanosoma cruzi and Leishmania donovani, and the latter were progressed into the murine model of infection. Despite the potent in vitro activity, there was no effect on parasitemia, necessitating further work to improve the pharmacokinetic properties of this series. Nonetheless, valuable insights have been obtained into the structure-activity and structure-property relationships of this compound series.

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

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.