β-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling

TY - JOUR

T1 - β-Carboline-3-carboxamide Antimalarials

T2 - Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling

AU - Mathew, Jopaul

AU - Zhou, Bo

AU - Haney, Reagan S.

AU - Kunz, Kevin A.

AU - Do Amaral, Leticia S.

AU - Roy Chowdhury, Rudraneel

AU - Butler, Joshua H.

AU - Li, Haibo

AU - Chakraborty, Amarraj J.

AU - Tabassum, Anika

AU - Bremers, Emily K.

AU - Merino, Emilio F.

AU - Coyle, Rachael

AU - Lee, Marcus C. S.

AU - Baud, Delphine

AU - Brand, Stephen

AU - Totrov, Maxim

AU - Cassera, Maria Belen

AU - Carlier, Paul R.

N1 - Publisher Copyright: © 2024 American Chemical Society.

PY - 2024/11/8

Y1 - 2024/11/8

N2 - The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline 1a was orally efficacious in Plasmodium berghei-infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a. The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a, is twice as potent as 1a. Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a, 1m, 42a, and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

AB - The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline 1a was orally efficacious in Plasmodium berghei-infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a. The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a, is twice as potent as 1a. Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a, 1m, 42a, and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

KW - ADME-Tox

KW - anti-infective

KW - malaria

KW - resistance profiling

KW - small-molecule inhibitor

UR - https://www.scopus.com/pages/publications/85208757353

U2 - 10.1021/acsinfecdis.4c00653

DO - 10.1021/acsinfecdis.4c00653

M3 - Article

C2 - 39466084

AN - SCOPUS:85208757353

SN - 2373-8227

VL - 10

SP - 3951

EP - 3962

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 11

ER -