Probing the B- & C-rings of the antimalarial tetrahydro-ß-carboline MMV008138 for steric and conformational constraints.
Bioorg Med Chem Lett
; 30(22): 127520, 2020 11 15.
Article
em En
| MEDLINE
| ID: mdl-32898696
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Pipecólicos
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Plasmodium falciparum
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Carbolinas
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Antimaláricos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article