Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids

• Published in: Bioorganic & medicinal chemistry 2008-06, Vol.18 (11), p.3147-3151
• Main Authors: Torres-Gómez, Héctor, Hernández-Núñez, Emanuel, León-Rivera, Ismael, Guerrero-Alvarez, Jorge, Cedillo-Rivera, Roberto, Moo-Puc, Rosa, Argotte-Ramos, Rocío, Carmen Rodríguez-Gutiérrez, María del, Chan-Bacab, Manuel Jesús, Navarrete-Vázquez, Gabriel
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiprotozoal; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Bioisosteric replacement; Biological and medical sciences; Drug Design; Entamoeba; Entamoeba histolytica; Entamoeba histolytica - drug effects; Giardia; Giardia lamblia; Giardia lamblia - drug effects; Inhibitory Concentration 50; Leishmania mexicana; Leishmania mexicana - drug effects; Medical sciences; Metronidazole - pharmacology; Molecular Structure; Parasitic Sensitivity Tests; Pentamidine; Pentamidine - chemical synthesis; Pentamidine - chemistry; Pentamidine - pharmacology; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium berghei - drug effects; Structure-Activity Relationship; Trichomonas; Trichomonas vaginalis; Trichomonas vaginalis - drug effects
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.05.009

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 μM) 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 against G. 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.