The contending forces influencing the alkylation of 2-methyl-5-nitroimidazole are discussed. A method is described which yields principally the 1-alkylated 2-methyl-5-nitroimidazole isomers preferred for their superior efficacy in the chemotherapy of certain protozoan infections. A series is reported, bearing short aliphatic side chains which incorporate electronegative groups. Several sulfones in this series are potent, well-tolerated, orally effective antiprotozoal agents. One of these agents is in clinical trial, and has been assigned the nonproprietary name, imidazole.2
Attachment of p-benzophenone side chains at N1 was found to be one of the most effective modifications for enhancing the potency of 6-azauracil against a broad spectrum of coccidia in chickens. Compound 20 was about 1000-fold more potent than 6-azauracil. Structure-activity relationships paralleled those found in a previously reported series of related analogues containing diphenyl sulfide and sulfone side chains. Drug metabolism studies showed the ketones to be reduced rapidly to carbinols, which are the prevalent species in vivo.
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