Synthesis of novel norsufentanil analogs 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 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.

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

“…Yet novel fentanyl derivatives continue to appear. Researchers of various groups reported novel analogues, including those of norsufentanil [10], carfentanil amides [11] or acrylic derivatives [12]. Fentanyl scaffold has also been used in the design of bivalent (multitarget) compounds to create mixed μ-/δ-OR ligands [13,14,15], or molecules joining even more distant pharmacophores like opioid receptor agonist and FAAH/MAGL hydrolases inhibitors [16], or opioid and dopamine receptors D2/D3 ligands [17].…”

Combinatorial discovery of antibacterials via a feature-fusion based machine learning workflow

“…However, combinatorial libraries for target screening are typically limited in size ranging from tens to hundreds of compounds and tend to follow the pre-existing molecular scaffolds to raise the hit rate. 18,19 The attempt to exponentially expand the potential chemical space necessitates highthroughput pipelines to manage the huge pool of candidates such as DNA-encoded libraries 15,20 and micro-dispensers, 21 which has arisen concerns regarding cost efficiency. Furthermore, the process of analyzing the collected data and extracting meaningful insights remains a laborious task.…”

“… 15 The Ugi reaction (UR) merges equivalent carboxylic acid, amine, aldehyde, and isonitrile components into a peptoid backbone with pendant functional groups. 16 The bioactivity of Ugi products has been demonstrated in areas such as antiviral 17 and analgesic 18 research. However, combinatorial libraries for target screening are typically limited in size ranging from tens to hundreds of compounds and tend to follow the pre-existing molecular scaffolds to raise the hit rate.…”