β-Carboline-3-carboxamide Antimalarials: Structure–Activity Relationship, ADME-Tox Studies, and Resistance Profiling
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 <b>1a</b> was orally efficacious in <i>Plasmodium berghei</i>-infected mice and that it showed low cross-resistance between susceptible <i>Plasmodium falciparum</i> and four different drug-resistant strains. In this report, we describe the synthesis and <i>in vitro</i> antimalarial evaluation of 91 new derivatives of <b>1a</b>. 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 <b>42a</b>, is twice as potent as <b>1a</b>. Six potent analogues were assessed for their drug-like properties, and four of these were subjected to <i>in vitro</i> barcoded cross-resistance profiling. Compounds <b>1a</b>, <b>1m</b>, <b>42a</b>, and <b>42m</b> 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.
Authors
- Stephen Brand (ORCID: https://orcid.org/0000-0002-7010-5348)
- Reagan S. Haney (ORCID: https://orcid.org/0000-0002-2452-4103)
- Arjun Chakraborty
- Riyanka Roy Chowdhury (ORCID: https://orcid.org/0000-0003-3869-3407)
- Kevin A. Kunz
- Delphine Baud (ORCID: https://orcid.org/0009-0005-6745-233X)
- Emily K. Bremers (ORCID: https://orcid.org/0000-0002-9768-0211)
- María B. Cassera (ORCID: https://orcid.org/0000-0001-6341-3169)
- Paul R. Carlier (ORCID: https://orcid.org/0000-0002-6683-285X)
- Rachael Coyle (ORCID: https://orcid.org/0000-0001-5838-1086)
- Jopaul Mathew (ORCID: https://orcid.org/0000-0002-4712-1403)
- Maxim Totrov (ORCID: https://orcid.org/0000-0001-8594-274X)
- Joshua H. Butler
- Haibo Li (ORCID: https://orcid.org/0000-0002-9309-6632)
- Lee M (ORCID: https://orcid.org/0000-0002-4973-0915)
- Bo Zhou (ORCID: https://orcid.org/0000-0001-8138-8796)
- Emilio F. Merino (ORCID: https://orcid.org/0000-0002-5400-7377)
- Afshan Tabassum
- Leticia S. Do Amaral (ORCID: https://orcid.org/0000-0002-2861-216X)
Institutions
- University of Georgia (US)
- University of Dundee (GB)
- Wellcome Sanger Institute (GB)
- University of Illinois Chicago (US)
- Molsoft (United States) (US)
- Wellcome Centre for Anti-Infectives Research (GB)
- Medicines for Malaria Venture (CH)
- Virginia Tech (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00653
- Citations
- 3
- Primary Topic
- Synthesis and bioactivity of alkaloids
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Medicines for Malaria Venture
- National Institutes of Health
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases