Synthesis of Novel Norsufentanil Analogues via a Four-component Ugi Reaction and in Vivo, Docking, and QSAR Studies of their Analgesic Activity

Abstract

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four-component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure-activity relationship (QSAR) model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil, and norsufentanil.

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In this study eighteen novel bivalent opioid ligands were prepared by a multicomponent reaction. The in vivo evaluation of the synthesized compounds showed that many of them were most potent than sufentanil as a commercial analgesic drug. The experimental data were supported by the QSAR and docking studies.

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