Synthesis and antiprotozoal activity of cationic 2-phenylbenzofurans.
A series of cationically substituted 2-phenylbenzofurans 1- 49 have been synthesized, and their in vitro antiprotozoal properties against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, as well as cytotoxicity against mammalian cells, have been evaluated. Eight dications exhibited antitrypanosomal activities comparable to that of pentamidine and melarsoprol. Twenty-six compounds were more active than pentamidine, and seven dications demonstrated increased activities against P. falciparum than artemisinin. Five congeners were more active against L. donovani than pentamidine. Introduction of methoxy or hydroxy groups in the 7- and/or 2'-position afforded derivatives that were highly selective against T. b. rhodesiense, P. falciparum, and L. donovani. Fourteen 2-phenylbenzofurans displayed excellent in vivo efficacies in the acute mouse model of trypanosomiasis, curing 3/4 or 4/4 animals at 4 x 5 mg/kg. Diamidine 1 and di( N-isopropyl)amidine 45, administered at 4 x 1 mg/kg, exhibited potency comparable to that of melarsoprol, providing 3/4 and 2/4 cures, respectively.
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.
Stanislav A
SA
Bakunov
Svetlana M
SM
Bakunova
Tanja
T
Wenzler
Todd
T
Barszcz
Karl A
KA
Werbovetz
Reto
R
Brun
Richard R
RR
Tidwell
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002412:Cations / Q000737:chemistry; D004195:Disease Models, Animal; D007891:Leishmania / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014345:Trypanosoma / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy
D000981:Antiprotozoal Agents; D001572:Benzofurans; D002412:Cations