Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints. Issue 22 (15th November 2020)

• Record Type: Journal Article
• Authors: Ding, Sha; Ghavami, Maryam; Butler, Joshua H.; Merino, Emilio F.; Slebodnick, Carla; Cassera, Maria B.; Carlier, Paul R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 22(2020)
• Publication Date: 2020-11-15
• Subjects: PS Pictet-Spengler -- MEP methylerythritol phosphate -- IPP isopentenyl diphosphate -- DMAPP dimethylallyl diphosphate -- Pf Plasmodium falciparum -- RMSD root-mean-square deviation; Malaria -- Plasmodium -- MEP pathway -- PfIspD; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127520
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The antimalarial candidate MMV008138 (1a ) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, NMR spectroscopy and calculation were used to study the effects of these modifications on the conformation of the C-ring and orientation of the D-ring. Unfortunately, all the B- and C-ring analogs explored lost in vitro antimalarial activity. The possible role of steric effects and conformational changes on target engagement are discussed.