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

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

  • ACS Infect Dis. 2024 Nov 8;10(11):3951-3962. doi: 10.1021/acsinfecdis.4c00653.
Jopaul Mathew 1,  Bo Zhou 1 2,  Reagan S Haney 3,  Kevin A Kunz 2,  Leticia S Do Amaral 3,  Rudraneel Roy Chowdhury 1 2,  Joshua H Butler 3,  Haibo Li 1,  Amarraj J Chakraborty 1,  Anika Tabassum 1,  Emily K Bremers 3,  Emilio F Merino 3,  Rachael Coyle 4 5,  Marcus C S Lee 4 5,  Delphine Baud 6,  Stephen Brand 6,  Maxim Totrov 7,  Maria Belen Cassera 3,  Paul R Carlier 1 2 8
Affiliations

Affiliations

  • 1 Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, 1040 Drillfield Drive, Blacksburg, Virginia 24061, United States.
  • 2 Department of Pharmaceutical Sciences, University of Illinois Chicago, 833 S Wood Street, Chicago, Illinois 60612, United States.
  • 3 Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases, University of Georgia, 120 E. Green Street, Athens, Georgia 30602, United States.
  • 4 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, U.K.
  • 5 Biological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee DD1 4HN, U.K.
  • 6 Medicines for Malaria Venture, Geneva 1215, Switzerland.
  • 7 Molsoft LLC, 11999 Sorrento Valley Road, San Diego, California 92121, United States.
  • 8 Department of Chemistry, University of Illinois Chicago, 845 W Taylor Street, Chicago, Illinois 60607, United States.
PMID: 39466084 DOI: 10.1021/acsinfecdis.4c00653
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.

Keywords

ADME-Tox; anti-infective; malaria; resistance profiling; small-molecule inhibitor.

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