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Synthesis and Anti‐ Plasmodium Activity of Benzimidazole Analogues Structurally Related to Astemizole
Author(s) -
Roman Gheorghe,
Crandall Ian E.,
Szarek Walter A.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300172
Subject(s) - benzimidazole , astemizole , moiety , chemistry , stereochemistry , combinatorial chemistry , isocoumarin , selectivity , plasmodium berghei , pharmacology , biochemistry , biology , organic chemistry , malaria , immunology , catalysis
A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti‐ Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4‐fluorobenzyl and/or 4‐methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4‐fluorobenzyl group, and variation of the 4‐aminopiperidine moiety, were explored. In vitro evaluation of the anti‐ Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC 50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.