title: Trypanocidal activity of conformationally restricted pentamidine congeners.
abstract: A series of conformationally restricted congeners of pentamidine in which the flexible pentyl bridge of pentamidine was replaced by trans-1,2-bismethylenecyclopropyl, phenyl, pyridinyl, piperazinyl, homopiperazinyl, and piperidinyl groups were synthesized. The compounds were evaluated for trypanocidal activity in vitro and in vivo against one drug-sensitive and three drug-resistant trypanosome isolates. The DNA binding affinity of the compounds was also studied using calf thymus DNA and poly(dA-dT). The nature of the linker influenced the DNA binding affinity as well as the trypanocidal activity of the compounds. trans-1,2-Bis(4-amidinophenoxymethylene)cyclopropane (1) was over 25-fold more potent than pentamidine against the drug-resistant isolate KETRI 243As-10-3, albeit with comparable DNA binding affinity. N,N'-Bis(4-amidinophenyl)homopiperazine (8) was the most potent trypanocide in vitro against all four trypanosome isolates studied, but N,N'-bis(4-amidinophenyl)piperazine (6) was the most effective agent in vivo against both drug-sensitive and drug-resistant trypanosomes.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Avenue, Room 327E, Johnson Building, Memphis, Tennessee 38163, USA. idonkor@utmem.edu
authors.forename: Isaac O
authors.initials: IO
authors.lastname: Donkor
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Tao
authors.forename: Donna
authors.initials: D
authors.lastname: Rattendi
authors.forename: Schennella
authors.initials: S
authors.lastname: Lane
authors.forename: Marc
authors.initials: M
authors.lastname: Vargas
authors.forename: Burt
authors.initials: B
authors.lastname: Goldberg
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bacchi
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002412:Cations; D002417:Cattle; D004247:DNA / Q000737:chemistry; D004351:Drug Resistance; D005260:Female; D051379:Mice; D008968:Molecular Conformation; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011067:Poly dA-dT / Q000737:chemistry; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy
chemical_list: D000578:Amidines; D002412:Cations; C472799:N,N'-bis(4-amidinophenyl)piperazine; D010879:Piperazines; D014344:Trypanocidal Agents; D011067:Poly dA-dT; D010419:Pentamidine; D004247:DNA