Abstract
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.
Original language | English |
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Pages (from-to) | 3951-3962 |
Number of pages | 12 |
Journal | ACS Infectious Diseases |
Volume | 10 |
Issue number | 11 |
DOIs | |
State | Published - Nov 8 2024 |
Externally published | Yes |
Funding
P.R.C., M.B.C., and M.T. thank the National Institutes of Health (AI157445) for financial support. We also thank the National Institutes of Health T32-AI060546 for financial support to R.S.H., J.H.B., and E.K.B. and R25GM109435 for financial support to L.S.D.A. M.C.S.L. would like to thank the Medicines for Malaria Venture (RD-18-0005) for support. We thank Emily E. Stacy for synthesizing compounds 2g and 2i and Benjamin T. Blackburn for synthesizing compound 10a. The following reagent was obtained through MR4 as part of the BEI Resources Repository, NIAID, NIH: Plasmodium falciparum Dd2 strain, MRA-150, deposited by D. Walliker.
Keywords
- ADME-Tox
- anti-infective
- malaria
- resistance profiling
- small-molecule inhibitor