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Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints.

Authors
  • Ding, Sha1
  • Ghavami, Maryam1
  • Butler, Joshua H2
  • Merino, Emilio F2
  • Slebodnick, Carla1
  • Cassera, Maria B2
  • Carlier, Paul R3
  • 1 Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States. , (United States)
  • 2 Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, Georgia 30602, United States. , (Georgia)
  • 3 Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Sep 05, 2020
Pages
127520–127520
Identifiers
DOI: 10.1016/j.bmcl.2020.127520
PMID: 32898696
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2020. Published by Elsevier Ltd.

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