Dicationic dibenzofuran derivatives as anti-Pneumocystis carinii pneumoniaagents: synthesis, DNA binding affinity, and anti-P-carinii activity in animmunosuppressed rat model

Previous work from our laboratory shows that compounds with two cations lin ked by a carbazole spacer were highly potent anti-P. carinii agents. A prod rug approach designed to increase oral activity of the dicationic carbazole s by converting amidine groups to amidoxime groups was unsuccessful. The ri ng nitrogen was implicated as playing a role in the lack of activity of car bazole amidoximes. The current study was designed to determine if replaceme nt of the carbazole ring nitrogen by isosteric oxygen to form dibenzofurans would improve effectiveness of amidoxime prodrugs. Eight dibenzofuran dica tionic derivatives were synthesized and evaluated for anti-P. carinii activ ity in an immunosuppressed rat model. Since DNA binding has been hypothesiz ed to play a key role in antimicrobial activity of dicationic compounds, th e compounds were examined for their binding affinity to calf thymus DNA and a poly-dA . poly-dT oligomer. While several of the compounds were more pot ent anti-P. carinii agents than pentamidine, the corresponding amidoximes w ere significantly less effective than the amidoxime of pentamidine. No dire ct quantitative correlation was determined between DNA binding affinity and anti-P. carinii activity, but all active compounds were strong DNA binding agents. (C) Elsevier, Paris.