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

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.

Figure 1.

P. falciparum (Dd2 strain) EC₅₀ values of β-carboline carboxamide 1a and related compounds.

Figure 2.

Plots of ABS P. falciparum pEC₅₀ vs calculated log D (pH 7.4). Data points with a downward streak represent upper limits of pEC50, i.e pEC₅₀ < 5.9 (See Table S1 in the Supporting Information). A) All compounds in this paper possessing a basic N_β atom (see text). The sky blue rectangle encloses 11 compounds with calc. log D = 2.5. B) Only those compounds with pEC₅₀ > 6.

Scheme 1.

Synthesis of C1-phenyl and amide substitution variants of 2a.

Scheme 2.

Synthesis of C1-phenyl, alkyl and heteroaromatic variants of 2a

Scheme 3.

Synthesis of 1k and 1l.