Cationic antiprotozoal drugs. Trypanocidal activity of 2-(4'-formylphenyl)imidazo[1,2-a]pyridinium guanylhydrazones and related derivatives of quaternary heteroaromatic compounds

Abstract

A series of quaternary 2-phenylimidazo[1,2-a]pyridinum salts has been prepared and evaluated for antiparasitic activity. Primary attention was focused on derivatives with amido, substituted hydrazone, and heterocyclic functionality at the para position of the phenyl substituent. Guanylhydrazones and N-substituted guanylhydrazones of the 4'-formyl-substituted compounds are very active against the blood state Trypanosoma rhodesiense in mice by subcutaneous or oral administration. The most potent compounds attain 100% survival for 30 days at doses of less than 1.0 mg/kg (sc) and greater than 5.0 mg/kg (po). Weaker activity is noted for certain other 4'-substituents such as carboxamidines and carboxamide oximes. Considerable variation in structure, including replacing of the imidazo [1,2-a]pyridinium ring by other cationic heterocyclic rings and insertion of linking groups between the heterocyclic ring and phenyl group, can be done, and a high level of activity is maintained. Relationships between these structural changes and biological activity are discussed.

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

“…Many of the diamidine derivatives have been investigated as anti-P. carinii drugs (21,34), but little attention has been paid to the guanylhydrazones. The availability of structure-activity data concerning the effects of guanylhydrazones on trypanosomes (33) should be of help in developing anti-P. carinii drugs. Our experience with gua-nylhydrazone derivatives in the rat model of pneumocystosis will be reported in detail in a separate publication.…”

“…The most active drugs included selected guanylhydrazone derivatives; diminazine, a diamidine; imidocarb, a carbanilide; and quinapyramine, an aminoquinaldine. The guanylhydrazone A compounds were synthesized by procedures of Ulrich et al (35), whereas the guanylhydrazone B derivatives were prepared by Richard Sundberg, University of Virginia (33). Pentamidine and five other compounds exhibited moderate activity.…”

Petite mutagenesis in Saccharomyces cerevisiae by a series of bis-cationic trypanocidal drugs

“…All of the compounds which are active trypanocides induce mutagenesis. There appears to be a correlation between trypanocidal activity and mutagenic activity which may have its structural origin in the spatial separation of the cationic centers.A series of imidazo[1,2-a]pyridinium and related heteroaromatic salts was recently reported to have good activity against the bloodstream form of Trypanosoma rhodesiense in mice (22). The structures of these compounds resemble those of various bis-cationic antitumor compounds such as diamidines, phthalanilides, and bis-quaternary ammonium heterocycles (1), which are generally believed to interact with DNA by binding in the minor groove (6, 11-13 For all experiments, the 1-ml sample was thawed, added to 10 ml of fresh medium, and grown for exactly 2 h before use.…”

“…A series of imidazo[1,2-a]pyridinium and related heteroaromatic salts was recently reported to have good activity against the bloodstream form of Trypanosoma rhodesiense in mice (22). The structures of these compounds resemble those of various bis-cationic antitumor compounds such as diamidines, phthalanilides, and bis-quaternary ammonium heterocycles (1), which are generally believed to interact with DNA by binding in the minor groove (6,(11)(12)(13).…”

Theoretical and experimental 13C and 15N NMR investigation of guanylhydrazones in solution

“…5 We have shown that aromatic guanylhydrazones are also active against the trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. 6 In previous papers, we reported that the three isomeric nitrobenzaldehyde guanylhydrazones (NBGH) (Fig.…”