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.
Patrick
D A
DA
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, 27599, USA.
Hall
J E
JE
Bender
B C
BC
McCurdy
D R
DR
Wilson
W D
WD
Tanious
F A
FA
Saha
S
S
Tidwell
R R
RR
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