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

  • ACS Infect Dis. 2025 Mar 14;11(3):584-599. doi: 10.1021/acsinfecdis.4c00666.
Andrew Spaulding  1 ,  Amrita Sharma  2 ,  Miriam A Giardini  3 ,  Benjamin Hoffman  2 ,  Jean A Bernatchez  3 ,  Laura-Isobel McCall  3 ,  Claudia M Calvet  3 ,  Jasmin Ackermann  3 ,  Julia M Souza  3 ,  Diane Thomas  3 ,  Caroline C Millard  1 ,  William G Devine  1 ,  Baljinder Singh  1 ,  Everton M Silva  3 ,  Susan E Leed  4 ,  Norma E Roncal  4 ,  Erica C Penn  4 ,  Jessey Erath  5 ,  Gaurav Kumar  2 ,  Yadira Sepulveda  3 ,  Arnold Garcia  3 ,  Ana Rodriguez  5 ,  Nelly El-Sakkary  3 ,  Richard J Sciotti  4 ,  Robert F Campbell  4 ,  Jeremiah D Momper  3 ,  James H McKerrow  3 ,  Conor R Caffrey  3 ,  Jair L Siqueira-Neto  3 ,  Michael P Pollastri  1 ,  Kojo Mensa-Wilmot  2 ,  Lori Ferrins  1  6
Affiliations
  • 1. Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
  • 2. Department of Molecular and Cellular Biology, Kennesaw State University, Science Building MailDrop1201, 370 Paulding Avenue, Kennesaw, Georgia 30144, United States.
  • 3. Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States.
  • 4. Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, United States.
  • 5. Department of Microbiology, New York University School of Medicine, 430 E. 29th Street, New York, New York 10010, United States.
  • 6. Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
PMID: 39936822 DOI: 10.1021/acsinfecdis.4c00666
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.

Keywords
Chagas disease; drug repurposing; human African trypanosomiasis; leishmaniasis; neglected tropical diseases; schistosomiasis.
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