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. 2024 Dec 13;10(12):4291-4300.
doi: 10.1021/acsinfecdis.4c00659. Epub 2024 Nov 11.

Tambjamines as Fast-Acting Multistage Antimalarials

Amrendra Kumar  1 , Yuexin Li  2 , Rozalia A Dodean  1   2 , Alison Roth  3 , Diana Caridha  3 , Michael S Madejczyk  3 , Xiannu Jin  3 , William E Dennis  3 , Patricia J Lee  3 , Brandon S Pybus  3 , Monica Martin  3 , Kristina Pannone  3 , Hieu T Dinh  3 , Cameron Blount  3 , Ravi Chetree  3 , Jesse DeLuca  3 , Martin Evans  3 , Robert Nadeau  3 , Chau Vuong  3 , Susan Leed  3 , Chad Black  3 , Jason Sousa  3 , Christina Nolan  3 , Frida G Ceja  4 , Stephanie A Rasmussen  4 , Patrick K Tumwebaze  5 , Philip J Rosenthal  6 , Roland A Cooper  4 , Matthias Rottmann  7   8 , Pamela Orjuela-Sanchez  9 , Stephan Meister  9 , Elizabeth A Winzeler  9 , Michael J Delves  10   11 , Holly Matthews  10 , Jake Baum  10   12 , Robert W Kirby  13 , Jeremy N Burrows  14 , James Duffy  14 , David H Peyton  1 , Kevin A Reynolds  1 , Jane X Kelly  1   2 , Papireddy Kancharla  1
Affiliations

Tambjamines as Fast-Acting Multistage Antimalarials

Amrendra Kumar et al. ACS Infect Dis. .

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.

Keywords: antimalarials; antiplasmodial; fast-acting; multistage; natural products; tambjamines.

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Conflict of interest statement

The authors declare no competing financial interest.

The material has been reviewed by the Walter Reed Army Institute of Research (WRAIR). There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be constructed as official or as reflecting the true views of the Department of the Army or the Department of Defense.

Figures

Figure 1.
Figure 1.
Percentage of parasite survival after 1 treatment and standard antimalarials.
Figure 2.
Figure 2.
(A) In vivo efficacy of 1 (KAR425) against P. falciparum Pf3D70087/N. The arrows indicated the days of treatment. The efficacy estimated was expressed as the reduction (in %) of parasitemia at day 7 after infection (n=1 mouse per dose of 1) as compared to the untreated control group (n=4). (B) Blood concentration profile of 1 after oral administration in mice.
Figure 3.
Figure 3.
Ex vivo activity of 1, 2, 5 and 14 and control antimalarial drugs against P. falciparum clinical isolates in Uganda. Data are presented as geometric mean ± 95% CI. DHA, dihydroartemisinin; CQ, chloroquine; PIP, piperaquine; MDAQ, monodesethyl-amodiaquine; MEF, mefloquine; PYD, pyronaridine; ATQ, atovaquone; LUM, lumefantrine.
Figure 4.
Figure 4.
Metabolite profiles of representative TAs 2 and 9 in human and mouse liver microsomes.
Figure 5.
Figure 5.
Biological and chemical stability of compound 1.
Scheme 1.
Scheme 1.
General Synthetic Route and Chemical Structures of Target TAs 1–14.
See this image and copyright information in PMC

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