Structure-activity study of pentamidine analogues as antiprotozoal agents.
Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM). Nine congeners (2-4, 12, 27, 30, and 64-66) were more active against P. falciparum than artemisinin (IC(50) = 6 nM). Eight compounds (12, 32, 33, 44, 59, 62, 64, and 66) exhibited equal or better antileishmanial activities than 1 (IC(50) = 1.8 microM). Several congeners were more active than 1 in vivo, curing at least 2/4 infected animals in the acute mouse model of trypanosomiasis. The diimidazoline 66 was the most promising compound in the series, showing excellent in vitro activities and high selectivities against T. b. rhodesiense, P. falciparum, and L. donovani combined with high antitrypanosomal efficacy in vivo.
Bakunova
Svetlana M
SM
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Bakunov
Stanislav A
SA
Patrick
Donald A
DA
Kumar
E V K Suresh
EV
Ohemeng
Kwasi A
KA
Bridges
Arlene S
AS
Wenzler
Tanja
T
Barszcz
Todd
T
Jones
Susan Kilgore
SK
Werbovetz
Karl A
KA
Brun
Reto
R
Tidwell
Richard R
RR
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002103:Cadaverine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy
C540185:1,5-bis(4-(2-imidazolinyl)benzene-1-amino)pentane; D000962:Antimalarials; D007093:Imidazoles; D014344:Trypanocidal Agents; D010419:Pentamidine; D002103:Cadaverine