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

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

Abstract:

Tetrahydro-β-carboline 1 (MMV008138)^1,2 controls growth of blood-stage Plasmodium falciparum by inhibiting a critical metabolic enzyme (IspD).^3-5 It has a very specific D-ring structure-activity relationship, requiring halogen-disubstitution at the 2?- and 4?-positions.^2,5 It also cannot tolerate methyl substitution at positions 1-3 of the C-ring or 9 of the B-ring.⁶ 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

Biography:

Haibo Li has been obtained his bachelor’s degree in Shandong Normal Unveristy, China in 2014. He then graduated in University of Denver with a master’s degree, USA in 2017. He is a Ph.D candidate in Virginia Tech, USA.