Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans

Abstract

Eighteen substituted 2,5-bis(4-guanylphenyl)furans and related analogues, including masked amidines in which the guanyl function is incorporated into a heterocyclic ring, were synthesized and their antimalarial and antitrypanosomal activity was evaluated. None of the compounds exhibited high orders of antimalarial activity, but 11 were very active against Trypanosoma rhodesiense in mice. Six compounds, including 2,5-bis(4-guanylphenyl)furan (4) and its 3-chloro, 3,4-dichloro, 3-methyl, 3,4-dimethyl and 3-chloro-4-methyl derivatives, produced cures in mice at submilligram dosage levels; the 3,4-dimethyl analogue exhibited a prolonged curative effect providing protection for 30 days after a single dose against a challenge by T. rhodesiense. These 6 compounds are somewhat more active in this screen than stilbamidine, hydroxystilbamidine and pentamidine. The masked amidines generally exhibited lower antitrypanosomal activity than their true guanyl counterparts. Compound 4 was synthesized from 1,4-di-p-bromophenyl-1,4-butanedione by cyclodehydrative furanization to 2,5-bis(4-bromophenyl)furan (2) which was allowed to react with Cu2(CN)2 to produce the corresponding bis-nitrile. The latter compound was ultimately converted by way of an imidate ester into 4. Similarly, the 3- and/or 4-substituted derivatives of 2 were employed to prepare the other members of the series.