Synthesis and anti-Pneumocystis carinii pneumonia activity of novel dicationic dibenzothiophenes and orally active prodrugs

Dicationic carbazoles have been found to be highly active against a rat mod el of Pneumocystis carinii pneumonia (PCP) Unfortunately, amidoxime derivat ives, designed as prodrugs, were inactive against PCP even though the corre sponding amidines were highly active. In the present work, a series of 2,8- and 3,7-bis cationic dibenzothiophenes was synthesized and assayed for ant i-PCP activity. Three of the compounds proved to be more potent and less to xic than a standard anti-PCP drug (pentamidine) when given intravenously. U nlike the carbazoles, a dibenzothiophene amidoxime prodrug given orally red uced the parasite load by more than 99%. While no quantitative correlation was seen between anti-PCP activity and DNA binding, a strong level of DNA b inding was found to be necessary for antimicrobial activity. (C) 1999 Editi ons scientifiques et medicales Elsevier SAS.