Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors

Baljinder Singh; Jean A Bernatchez; Laura-Isobel McCall; Claudia M Calvet; Jasmin Ackermann; Julia M Souza; Diane Thomas; Everton M Silva; Kelly A Bachovchin; Dana M Klug; Hitesh B Jalani; Seema Bag; Melissa J Buskes; Susan E Leed; Norma E Roncal; Erica C Penn; Jessey Erath; Ana Rodriguez; Richard J Sciotti; Robert F Campbell; James McKerrow; Jair L Siqueira-Neto; Lori Ferrins; Michael P Pollastri

doi:10.1021/acsmedchemlett.9b00453

Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors

ACS Med Chem Lett. 2020 Jan 10;11(3):249-257. doi: 10.1021/acsmedchemlett.9b00453. eCollection 2020 Mar 12.

Authors

Baljinder Singh¹, Jean A Bernatchez², Laura-Isobel McCall², Claudia M Calvet², Jasmin Ackermann², Julia M Souza², Diane Thomas², Everton M Silva², Kelly A Bachovchin¹, Dana M Klug¹, Hitesh B Jalani¹, Seema Bag¹, Melissa J Buskes¹, Susan E Leed³, Norma E Roncal³, Erica C Penn³, Jessey Erath⁴, Ana Rodriguez⁴, Richard J Sciotti³, Robert F Campbell³, James McKerrow², Jair L Siqueira-Neto², Lori Ferrins¹, Michael P Pollastri¹

Affiliations

¹ Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
² Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States.
³ Experimental Therapeutics, Walter Reed Army Institute of Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.
⁴ Department of Microbiology, New York University School of Medicine, 430 East 29th Street, New York, New York 10010, United States.

Abstract

Utilizing a target repurposing and parasite-hopping approach, we tested a previously reported library of compounds that were active against Trypanosoma brucei, plus 31 new compounds, against a variety of protozoan parasites including Trypanosoma cruzi, Leishmania major, Leishmania donovani, and Plasmodium falciparum. This led to the discovery of several compounds with submicromolar activities and improved physicochemical properties that are early leads toward the development of chemotherapeutic agents against kinetoplastid diseases and malaria.