Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids.
A series of ten novel hybrids from benzimidazole and pentamidine were prepared using a short synthetic route. Each compound was tested in vitro against the protozoa Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, Leishmania mexicana, and Plasmodium berghei, in comparison with pentamidine and metronidazole. Some analogues showed high bioactivity in the low micromolar range (IC(50)<1 microM) against the first four protozoa, which make them significantly more potent than either standard. 1,5-bis[4-(5-methoxy-1H-benzimidazole-2-yl)phenoxy]pentane (2) was 3- and 9-fold more potent againstG. lamblia than metronidazole and pentamidine, respectively. This compound was 23-, 108-, and 13-fold more active than pentamidine against T. vaginalis, E. histolytica and L. mexicana, respectively. Studying further structure-activity relationships through the use of bioisosteric substitution in these hybrids should provide new leads against protozoal diseases.
Torres-Gómez
Héctor
H
Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico.
Hernández-Núñez
Emanuel
E
León-Rivera
Ismael
I
Guerrero-Alvarez
Jorge
J
Cedillo-Rivera
Roberto
R
Moo-Puc
Rosa
R
Argotte-Ramos
Rocío
R
Rodríguez-Gutiérrez
María Del Carmen
Mdel C
Chan-Bacab
Manuel Jesús
MJ
Navarrete-Vázquez
Gabriel
G
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004748:Entamoeba histolytica / Q000187:drug effects; D016829:Giardia lamblia / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects; D008795:Metronidazole / Q000494:pharmacology; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects; D013329:Structure-Activity Relationship; D014246:Trichomonas vaginalis / Q000187:drug effects
C529685:1,5-bis(4-(5-methoxy-1H-benzimidazole-2-yl)phenoxy)pentane; D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D008795:Metronidazole; D010419:Pentamidine