Analogs of pentamidine as potential anti-Pneumocystis chemotherapeutics

A series of 20 pentamidine analogs were prepared using 2 general Schemes that evaluated heteroatoms, sulfobenzene and alkanediamide groups in the aliphatic linker and methoxy substituents attached to the benzene rings for efficacy against the fungal pathogen, Pneumocystis carinii in an ATP bioassay. All but one of the 20 bisamidines reduced the ATP content of the P. carinii over the 72 h of the assay period. The highest activities were associated with the lack of methoxy groups and the presence of the O, N and S heteroatoms. Activity (IC50) for compounds 1, 5, 6, 10 ranged from 1.1 to 2.13 μM. The compound 11 with similar activity (1.33 μM), bears a sulfobenzene group at a nitrogen in the aliphatic linker. The alkanediamide-linked bisbenzamidines showed a moderate inhibition of ATP. Generally, the inclusion of a heteroatom in the aliphatic linker and absence of methoxy groups at the benzene rings were associated with higher activities in this assay. Of note, most of the compounds had little to no cytotoxicity in mammalian cell cultures. Although not quite as potent as other pentamidine derivatives, these compounds hold promise for decreased side effects within the mammalian host.

Graphical abstractPentamidine analogs were prepared and analyzed for efficacy against Pneumocystis carinii. In ATP bioassay they showed marked or moderate activity. Most of them had no cytotoxicity in mammalian cell cultures. Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 20 pentamidine analogs were prepared with high yield and purity. ► All were evaluated for efficacy against Pneumocystis carinii in an ATP bioassay. ► Heteroatoms in linker and absence of methoxy groups on benzene were associated with higher activities. ► These compounds hold promise for decreased side effects within the mammalian host.