title: Synthesis and anti-Plasmodium activity of benzimidazole analogues structurally related to astemizole.
abstract: 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 IC50 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.
authors.affiliation: Department of Chemistry, Queen's University, Chernoff Hall, 90 Bader Lane, Kingston, ON K7L 3N6 (Canada); Current address: Petru Poni Institute of Macromolecular Chemistry, 41A Aleea Gr. Ghica Vodă, Iaşi 700487 (Romania). gheorghe.roman@icmpp.ro.
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Roman
authors.forename: Ian E
authors.initials: IE
authors.lastname: Crandall
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016589:Astemizole / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D001562:Benzimidazoles; D016589:Astemizole; C031000:benzimidazole
keywords: Plasmodium falciparum; antiprotozoal agents; astemizoles; benzimidazoles; structure-activity relationships