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 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.
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, 27599, USA.
D A
DA
Patrick
J E
JE
Hall
B C
BC
Bender
D R
DR
McCurdy
W D
WD
Wilson
F A
FA
Tanious
S
S
Saha
R R
RR
Tidwell
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D004271:DNA, Fungal / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000627:therapeutic use*; D051381:Rats; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000627:therapeutic use*
D000935:Antifungal Agents; D004271:DNA, Fungal; D011355:Prodrugs; D013876:Thiophenes