Pentamidine Congeners. 2. 2-Butene-Bridged Aromatic Diamidines and Diimidazolines as Potential Anti-Pneumocystis carinii Pneumonia Agents

We have synthesized cis and trans geometric isomers 1-8 as semirigid congeners of pentamidine. Compounds 1-4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5-8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1-4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA).poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.