Synthesis and antitrypanosomal activity of some bis(4-guanylphenyl) five- and six-membered ring heterocycles

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Abstract
2,5-Bis(4-guanylphenyl)-1,3-oxazole, 2,5-bis(4-guanylphenyl)-1,3,4-oxadiazole and -1,3,4-thiadiazole, and 3,6-bis(4-guanylphenyl)pyridazine and several of their cyclic guanyl analogues were synthesized. 2,5-Bis(4-guanylphenyl)-1,3-oxazole and -1,3,4-thiadiazole showed good activity, without acute toxicity, against Trypanosoma rhodesiense in mice, producing cures at a 3 mg/kg dosage level. This activity is comparable to stilbamidine, hydroxystilbamidine and pentamidine in this test. In contrast, 2,5-bis(4-guanylphenyl)-1,3,4-oxadiazole shows a sharp reduction in activity. Generally, the cyclic guanyl analogues exhibit low orders of activity and toxicity begins to appear at moderate dosage levels. All guanyl and cyclic guanyl compounds were synthesized from bisnitrile precursors by way of imidate ester hydrochlorides in a classical Pinner-type approach.