Synthesis and SAR of alkanediamide-linked bisbenzamidines with anti-trypanosomal and anti-pneumocystis activity.
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.
Huang
Tien L
TL
Xavier University of Louisiana, College of Pharmacy, 1 Drexel Drive, New Orleans, LA 70125, USA. thuang@xula.edu
Vanden Eynde
Jean Jacques
JJ
Mayence
Annie
A
Collins
Margaret S
MS
Cushion
Melanie T
MT
Rattendi
Donna
D
Londono
Indira
I
Mazumder
Lakshman
L
Bacchi
Cyrus J
CJ
Yarlett
Nigel
N
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
D000578:Amidines; D000813:Anilides; D000981:Antiprotozoal Agents; D001550:Benzamidines; C546011:N,N'-bis(4-(aminoiminomethyl)phenyl)hexanediamide; D003958:Diamide