title: Synthesis and SAR of alkanediamide-linked bisbenzamidines with anti-trypanosomal and anti-pneumocystis activity.
abstract: A series of alkanediamide-linked bisbenzamidines was synthesized and tested in vitro against a drug-sensitive strain of Trypanosoma brucei brucei, a drug-resistant strain of Trypanosoma brucei rhodesiense and Pneumocystiscarinii. Bisbenzamidines linked with longer alkanediamide chains were potent inhibitors of both strains of T. brucei. However, bisbenzamidines linked with shorter alkanediamide chains were the most potent compounds against P. carinii. N,N'-Bis[4-(aminoiminomethyl)phenyl] hexanediamide, 4 displayed potent inhibition (IC50=2-3 nM) against T. brucei and P. carinii, and was non-cytotoxic in the A549 human lung carcinoma cell line. The inhibitory bioactivity was significantly reduced when the amidine groups in 4 were moved from the para to the meta positions or replaced with amides.
authors.affiliation: Xavier University of Louisiana, College of Pharmacy, 1 Drexel Drive, New Orleans, LA 70125, USA. thuang@xula.edu
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Vanden Eynde
authors.forename: Annie
authors.initials: A
authors.lastname: Mayence
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Collins
authors.forename: Melanie T
authors.initials: MT
authors.lastname: Cushion
authors.forename: Donna
authors.initials: D
authors.lastname: Rattendi
authors.forename: Indira
authors.initials: I
authors.lastname: Londono
authors.forename: Lakshman
authors.initials: L
authors.lastname: Mazumder
authors.forename: Cyrus J
authors.initials: CJ
authors.lastname: Bacchi
authors.forename: Nigel
authors.initials: N
authors.lastname: Yarlett
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D003958:Diamide / Q000737:chemistry*; D006801:Humans; D011010:Pneumocystis / Q000187:drug effects; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
chemical_list: D000578:Amidines; D000813:Anilides; D000981:Antiprotozoal Agents; D001550:Benzamidines; C546011:N,N'-bis(4-(aminoiminomethyl)phenyl)hexanediamide; D003958:Diamide