Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents.
A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bis-guanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c-f were obtained in three steps starting by reacting the diamines 4a,b with ethyl isothiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a-f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c-f were obtained via the base catalyzed decarbamoylation of 8a-f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by DeltaT(m) values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.
Arafa
Reem K
RK
Department of Chemistry, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA.
Ismail
Mohamed A
MA
Munde
Manoj
M
Wilson
W David
WD
Wenzler
Tanja
T
Brun
Reto
R
Boykin
David W
DW
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D015996:Survival Rate; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*
D000981:Antiprotozoal Agents; D006146:Guanidines; D011355:Prodrugs; D004247:DNA