title: In vitro antiamoebic activity evaluation and docking studies of metronidazole-triazole hybrids.
abstract: An in-house database of 520 compounds was docked against Entamoeba histolytica thioredoxin reductase (EhTrR), a promising target for the treatment of amoebiasis. Amongst these, some metronidazole (MTZ)-triazole hybrids were ranked high, with docking scores from -10.23 to -7.56. Studies of the binding orientations and conformations show that the head groups of MTZ-triazole hybrids interact with the arginine residues within the binding pocket of EhTrR, making it clear that such is the optimal and most reliable orientation for this class of compounds. The top-ten MTZ-triazole hybrids were then selected for evaluation of their activity against the HM1:IMSS strain of amoeba. The most active compound, 2-pyridyl-(1,2,3-triazolyl)metronidazole 10, with an IC50 value of 8.4 nM, was significantly more active than the standard drug MTZ alone. Docking studies revealed that compound 10 may act as an EhTrR inhibitor with activity in the nanomolar range and satisfactory ADME properties; it is a suitable candidate to be carried forward as a potential lead in the discovery of drugs to combat amoebiasis.
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007 (India).
authors.forename: Beena
authors.initials: B
authors.lastname: Negi
authors.forename: K Kranthi
authors.initials: KK
authors.lastname: Raj
authors.forename: Shadab Miyan
authors.initials: SM
authors.lastname: Siddiqui
authors.forename: Dittakavi
authors.initials: D
authors.lastname: Ramachandran
authors.forename: Amir
authors.initials: A
authors.lastname: Azam
authors.forename: Diwan S
authors.initials: DS
authors.lastname: Rawat
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D004748:Entamoeba histolytica / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008795:Metronidazole / Q000737:chemistry*; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry* / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000981:Antiprotozoal Agents; D014230:Triazoles; D008795:Metronidazole; D013880:Thioredoxin-Disulfide Reductase
keywords: Entamoeba histolytica; antiprotozoal agents; inhibitors; metronidazole; thioredoxin reductase