Patrick D A, Hall J E, Bender B C, McCurdy D R, Wilson W D, Tanious F A, Saha S, Tidwell R R
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, 27599, USA.
Eur J Med Chem. 1999 Jul-Aug;34(7-8):575-83. doi: 10.1016/s0223-5234(00)80027-6.
Dicationic carbazoles have been found to be highly active against a rat model of Pneumocystis carinii pneumonia (PCP). Unfortunately, amidoxime derivatives, designed as prodrugs, were inactive against PCP even though the corresponding amidines were highly active. In the present work, a series of 2,8- and 3,7-bis cationic dibenzothiophenes was synthesized and assayed for anti-PCP activity. Three of the compounds proved to be more potent and less toxic than a standard anti-PCP drug (pentamidine) when given intravenously. Unlike the carbazoles, a dibenzothiophene amidoxime prodrug given orally reduced 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 binding was found to be necessary for antimicrobial activity.
