Identification of Substituted 4-Aminocinnolines as Broad-Spectrum Antiparasitic Agents
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 <i>Trypanosoma cruzi</i> and <i>Leishmania donovani</i>, and the latter were progressed into the murine model of infection. Despite the potent <i>in vitro</i> 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.
Authors
- Diane Thomas (ORCID: https://orcid.org/0000-0003-3101-6606)
- Everton Morais da Silva (ORCID: https://orcid.org/0000-0003-3993-4954)
- Erica Penn
- Kojo Mensa‐Wilmot (ORCID: https://orcid.org/0000-0002-8325-7228)
- Benjamin U. Hoffman (ORCID: https://orcid.org/0000-0002-9831-4061)
- Conor R. Caffrey (ORCID: https://orcid.org/0000-0003-3048-8572)
- Yadira Sepulveda
- Susan E. Leed
- Andrew Spaulding
- Jean Bernatchez (ORCID: https://orcid.org/0000-0002-8309-1627)
- Baljinder Singh (ORCID: https://orcid.org/0000-0003-2828-5768)
- William G. Devine (ORCID: https://orcid.org/0000-0001-7718-3624)
- Nelly El‐Sakkary (ORCID: https://orcid.org/0000-0003-3357-0424)
- Jair L. Siqueira-Neto (ORCID: https://orcid.org/0000-0001-9574-8174)
- Jessey Erath (ORCID: https://orcid.org/0000-0001-8802-635X)
- Jorge Augusto Soares de Souza (ORCID: https://orcid.org/0000-0002-0922-3214)
- Richard J. Sciotti (ORCID: https://orcid.org/0000-0002-3069-3122)
- Lori Ferrins (ORCID: https://orcid.org/0000-0001-8992-0919)
- Arnold Garcia
- James H. McKerrow (ORCID: https://orcid.org/0000-0002-5152-4627)
- Michael P. Pollastri (ORCID: https://orcid.org/0000-0001-9943-7197)
- Miriam A. Giardini (ORCID: https://orcid.org/0000-0002-6510-2409)
- Jeremiah D. Momper (ORCID: https://orcid.org/0000-0002-3154-6685)
- Laura‐Isobel McCall (ORCID: https://orcid.org/0000-0002-1243-8953)
- Norma Roncal
- Jasmin Ackermann (ORCID: https://orcid.org/0000-0002-1275-1122)
- Cláudia M. Calvet (ORCID: https://orcid.org/0000-0003-1275-1226)
- Robert F. Campbell (ORCID: https://orcid.org/0000-0002-8745-2805)
- Gaurav Kumar (ORCID: https://orcid.org/0000-0002-8689-0782)
- Amrita Sharma
- Caroline C. Millard
- Ana Rodriguez
Institutions
- Northeastern University (US)
- Kennesaw State University (US)
- University of California San Diego (US)
- Center for Discovery (US)
- New York University (US)
- University of Montana (US)
- Universidad del Noreste (MX)
- Walter Reed Army Institute of Research (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00666
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Kennesaw State University
- York University
- National Institutes of Health
- School of Medicine, New York University
- University of California, San Diego
- National Institute of Allergy and Infectious Diseases
- Skaggs School of Pharmacy and Pharmaceutical Sciences