Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia.
A series of 33 analogues of the anti-Pneumocystis carinii drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) was synthesized for screening against a rat model of P. carinii pneumonia (PCP). Twenty-five of the compounds showed efficacy against PCP when compared to a saline-treated control group. Two compounds, 1,4-bis(4-amidinophenoxy)butane (butamidine, 6) and 1,3-bis(4-amidino-2-methoxyphenoxy)propane (DAMP, 16), were statistically more effective than the parent drug in treating PCP in the rat model of infection. In addition to their activity against PCP, the compounds were also evaluated for antitrypsin activity, ability to inhibit thymidylate synthetase, affinity for DNA, and toxicity. No correlation was observed between the tested molecular interactions of the diamidines and their effectiveness against PCP.
Tidwell
R R
RR
Department of Pathology, School of Medicine, University of North Carolina, Chapel Hill 27599.
Jones
S K
SK
Geratz
J D
JD
Ohemeng
K A
KA
Cory
M
M
Hall
J E
JE
D000578:Amidines / Q000138:chemical synthesis*; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis*; D001550:Benzamidines / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism; D008297:Male; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000627:therapeutic use
D000578:Amidines; D000890:Anti-Infective Agents; D001550:Benzamidines; D014361:Trypsin Inhibitors; C063539:butamidine; C063540:1,3-bis(4-amidino-2-methoxyphenoxy)propane; D010419:Pentamidine; D004247:DNA; D013940:Thymidylate Synthase