ABSTRACT
Spiro[aziridine-2,2'-adamantanes] 1 and 2, spiro[azetidine-2,2'-adamantanes] 3 and 5, spiro[azetidine-3,2'-adamantane] 13, spiro[piperidine-4,2'-adamantanes] 25 and 27, and spiro barbituric analog 18 were synthesized and tested for their anti-influenza A virus properties and for trypanocidal activity. The effect of ring size on potency was investigated. Piperidine 25 showed significant anti-influenza A virus activity, being 12-fold more active than amantadine, about 2-fold more active than rimantadine, and 54-fold more potent than ribavirin. It also proved to be the most active of the compounds tested against bloodstream forms of the African trypanosome, Trypanosoma brucei, being 1.5 times more potent than rimantadine and at least 25 times more active than amantadine.
Subject(s)
Adamantane/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Adamantane/chemistry , Adamantane/pharmacology , Animals , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Influenza A virus/drug effects , Leishmania/drug effects , Trypanosoma/drug effectsABSTRACT
It has been more than 25 years since it was first reported that nifurtimox and benznidazole promote superoxide production in trypanosomes. However, there has been no direct evidence of an association between the drug-induced free radicals and trypanocidal activity. Here, we identify a superoxide dismutase required to protect Trypanosoma brucei from drug-generated superoxide.
