Tambjamines as Fast-Acting Multistage Antimalarials.

Kumar, Amrendra; Li, Yuexin; Dodean, Rozalia A; Roth, Alison; Caridha, Diana; Madejczyk, Michael S; Jin, Xiannu; Dennis, William E; Lee, Patricia J; Pybus, Brandon S; +32 more... Martin, Monica; Pannone, Kristina; Dinh, Hieu T; Blount, Cameron; Chetree, Ravi; DeLuca, Jesse; Evans, Martin; Nadeau, Robert; Vuong, Chau; Leed, Susan; Black, Chad; Sousa, Jason; Nolan, Christina; Ceja, Frida G; Rasmussen, Stephanie A; Tumwebaze, Patrick K; Rosenthal, Philip J; Cooper, Roland A; Rottmann, Matthias; Orjuela-Sanchez, Pamela; Meister, Stephan; Winzeler, Elizabeth A; Delves, Michael J; Matthews, Holly; Baum, Jake; Kirby, Robert W; Burrows, Jeremy N; Duffy, James; Peyton, David H; Reynolds, Kevin A; Kelly, Jane X; Kancharla, Papireddy; (2024) Tambjamines as Fast-Acting Multistage Antimalarials. ACS infectious diseases, 10 (12). pp. 4291-4300. ISSN 2373-8227 DOI: https://doi.org/10.1021/acsinfecdis.4c00659

Abstract

Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages. Notably, our lead candidate 1 (KAR425) displays excellent oral efficacy with complete clearance of parasites within 72 h of treatment in the humanized Plasmodium falciparum (NOD-scid) mouse model at 50 mg/kg × 4 days. Profiling of compound 1 demonstrated a fast in vitro killing profile. In addition, several other tambjamine analogues cured erythrocytic Plasmodium yoelii infections after oral doses of 30 and 50 mg/kg × 4 days in a murine model while exhibiting good safety and metabolic profiles. This study presents the first account of multiple-stage antiplasmodial activities with rapid killing profile in the tambjamine family.

Additional Information

Item Type	Article
Faculty and Department	Faculty of Infectious and Tropical Diseases > Department of Infection Biology
Research Centre	Malaria Centre
PubMed ID	39526703
Elements ID	232746
Official URL	http://dx.doi.org/10.1021/acsinfecdis.4c00659

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