Tetrahydro-β-carboline 1 (MMV008138) controls growth of blood-stage Plasmodium falciparum by inhibiting a critical metabolic enzyme (IspD). It has a very specific D-ring structure-activity relationship, requiring halogen-disubstitution at the 2- and 4- positions. It also cannot tolerate methyl substitution at positions 1-3 of the C-ring or 9 of the B-ring. In this study we report the synthesis and evaluation of 19 A-ring variants of 1. Interestingly, extreme sensitivity to substitution is also seen in the A-ring, and only three derivatives had EC50 within 3-fold of the parent (20a, c, d). 7-Fluoro analog 20c showed a marked improvement in microsomal stability. However, this improvement did not improve oral efficacy in a mouse model of malaria. Finally, we use X-ray crystallography of (±)-21a and 1H NMR spectroscopy of 1 and 21a to address the equilibrium aqueous conformation of 1, and reevaluate a literature proposal for the binding pose of 1 in PfIspD.

A-ring modification on MMV008138: Effects on antimalarial potency and microsomal stability, implications for mode of inhibition

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