ABSTRACT
The synthesis of a series of 14 new 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2-ones from the 1,3-dipolar cycloaddition reaction of 1-allyl-4-(trihalomethyl)pyrimidin-2(1H)-ones with aryl nitrile oxides is described. Also, the antiproliferative activity of the title compounds was tested against five human tumoral cell lines: MCF-7 breast cancer cell line, ER+ (estrogen receptor positive); HepG-2 (hepatoma); T-24 (bladder cancer); HCT-116 cell (colorectal carcinoma); and CACO-2. The preliminary results are promising, since three compounds presented IC50 values below 2 µM, as well as moderate to high selectivity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Isoxazoles/pharmacology , Pyrimidinones/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HEK293 Cells , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Models, Molecular , Molecular Structure , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
To search for new cruzain inhibitors, the synthesis of a series of novel 2-(N'-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines in a convergent manner is presented. The cruzain inhibitory activity of some of these compounds was evaluated and a binding model was proposed. All derivatives tested were active and the most significant inhibitory effect (80% at 100 microM) and IC(50) value (85 microM) were obtained from the 2-(N'-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine. Although further structural optimization to improve solubility is necessary, the molecular docking studies suggest that these inhibitors occupy the S2 pocket without irreversible enzyme inactivation, through hydrophobic interactions, thus, indicating a desirable mode of interaction for the design of novel inhibitors.
