Highly active anti-Pneumocystis carinii compounds in a library of novel piperazine-linked bisbenzamidines and related compounds.
Trimethoprim-sulfamethoxazole and pentamidine isethionate have been used extensively for the prophylaxis and therapy of pneumonia caused by Pneumocystis jirovecii. Problems associated with toxicity and potential emerging resistance for both therapies necessitate the development of safe and effective analogs or new treatment strategies. In the present study, a library of 36 compounds was synthesized by using the pentamidine molecule as the parent compound modified by a 1,4-piperazinediyl moiety as the central linker to restrict conformation flexibility. The compounds were evaluated for anti-Pneumocystis carinii activity in a bioluminescent ATP-driven assay. Four of the compounds were highly active, with 50% inhibitory concentration (IC(50)) values of <0.01 microg/ml; four had very marked activity (IC(50) < 0.10 microg/ml); ten had marked activity (IC(50) < 1.0 microg/ml); nine had moderate activity (IC(50) < 10 microg/ml); one had slight activity (IC(50) = 34.1 microg/ml); and the remaining eight did not demonstrate activity in this assay system. The high level of activity was specifically associated with an alkyl chain length of five to six carbons attached to one of the nitrogens of the bisamidinium groups. None of the highly active compounds and only one of the very marked compounds exhibited any toxicity when evaluated in three mammalian cell lines. The strategy of substitution of 1,4-piperazine-linked bisbenzamidines produced compounds with the highest level of activity observed in the ATP assay and holds great promise for the development of efficacious anti-P. carinii therapy.
Cushion
Melanie T
MT
University of Cincinnati College of Medicine, Division of Infectious Diseases, 231 Albert Sabin Way, Cincinnati, OH 45267-0560, USA. melanie.cushion@uc.edu
Walzer
Peter D
PD
Collins
Margaret S
MS
Rebholz
Sandra
S
Vanden Eynde
Jean Jacques
JJ
Mayence
Annie
A
Huang
Tien L
TL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001550:Benzamidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007202:Indicators and Reagents; D008156:Luciferases; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D045363:Pneumocystis carinii / Q000187:drug effects*; D051381:Rats; D011914:Rats, Inbred BN; D020318:Rats, Long-Evans; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001550:Benzamidines; D007202:Indicators and Reagents; D010879:Piperazines; D000255:Adenosine Triphosphate; D008156:Luciferases