stilbamidine and Trypanosomiasis

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, have been synthesized and their antimalarial and antitrypanosomal activity has been evaluated. None of the compounds exhibited high orders of antimalarial activity; however, 11 were very active against Trypanosoma rhodesiense in mice. Six compounds, including 2,5-bis(4-guanylphenyl)furan (4) and its 3-chloro (32), 3,4-dichloro (31), 3-methyl (25), 3,4-dimethyl (20), and 3-chloro-4-methyl (38) derivatives, produced cures in mice at submilligram dosage levels; the 3,4-dimethyl (20) analogue exhibited a prolonged curative effect providing protection for 30 days after a single dose against a challenge by T. rhodesiense. These six 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 3. 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.

Topics: Animals; Antimalarials; Antiprotozoal Agents; Furans; Malaria; Mice; Plasmodium berghei; Structure-Activity Relationship; Trypanocidal Agents; Trypanosomiasis

[(14)C]Stilbamidine was used to study the distribution of the drug in the organs and tissues of rats following intravenous injection. The prophylactic action of stilbamidine was shown to depend upon the unchanged drug retained in tissues, especially the liver. Only the parent drug was extracted from trypanosomes when an infection was treated during the acute phase, as shown by the use of the fluorescent properties of stilbamidine in conjunction with scanning and chromatographic techniques. The action of stilbamidine on trypanosomes is therefore a direct one. A method for the synthesis of [(14)C]stilbamidine in much improved yield is also described.

Topics: Animals; Injections, Intravenous; Rats; Stilbamidines; Stilbenes; Trypanosomiasis

Topics: Amidines; Aniline Compounds; Animals; Coloring Agents; Diminazene; Quinolinium Compounds; Stilbamidines; Trypanosoma; Trypanosomiasis

Topics: Humans; Stilbamidines; Stilbenes; Trypanosoma; Trypanosomiasis