Design, synthesis, in-vivo, and in-silico studies of 1,2,3-triazole tethered derivatives of morphine as novel anti-nociceptive agents.

Abstract

Due to the use of morphine as a well-known analgesic, a semi-synthesis of its newer triazole derivatives was performed in this project. Several derivatives were analyzed via molecular docking and a set of target molecules with acceptable docking scores were selected for the synthesis. The project focused on targeting one of the pharmacophores of morphine. The phenolic hydroxy group of morphine was reacted with propargyl bromide to furnish the terminal alkyne. This compound, as starting material for the click reaction underwent 1,3-dipolar cycloaddition reaction with different azides to produce the target 1,2,3-triazole tethered derivatives of morphine. The anti-nociceptive properties of the products were evaluated by tail flick test. It was observed that compounds 3b, 3d, and 3k with (ED50 = 0.23 mg/kg) showed superior pain relief activities in comparison with morphine (ED50 = 0.69 mg/kg). Finally, computational ADME/T studies were performed via SwissADME web server to gain a better understanding of the pharmacokinetics of the synthesized compounds in humans.