Structural Characterization and Antidiabetic Drug Potential of Aminated Eugenol Derivatives Synthesized via Ultrasound-Assisted Method

Abstract

ABSTRACT. Diabetes mellitus remains a global health challenge, necessitating the development of more effective a-amylase inhibitors with fewer side effects than current synthetic drugs. This study reports the successful synthesis of three aminated eugenol derivatives, a (1-(4-allyl-2-methoxyphenoxy)-3-(phenylamino)propan-2-ol), b (1-(4-allyl-2-methoxyphenoxy)-3-(m-tolylamino)propan-2-ol), and c (1-(4-allyl-2-methoxyphenoxy)-3-((4 chlorophenyl)amino)propan-2-ol), via ultrasonically assisted epoxide ring-opening using aniline, m-toluidine, and 4-chloroaniline. Ultrasonic irradiation significantly reduced the reaction time from 5-24 hours to 2 hours. Structural characterization by FTIR, ¹H-NMR, ¹³C-NMR, GC-MS, and melting point analysis confirmed the successful formation of all derivatives. In vitro α-amylase inhibition assays (UV–Vis) showed that all compounds exhibited higher inhibitory activity than acarbose, with compound b demonstrating the strongest inhibition (99.04% at 250 µM). Molecular docking studies against α-amylase (PDB: 1B2Y) further supported these results, yielding binding energies of –4.58, –5.13, and –5.16 kcal mol⁻¹ for compounds a, b, and c, respectively, compared with –3.64 kcal mol⁻¹ for acarbose. These findings demonstrate the enhanced efficiency of the ultrasound-assisted synthesis and substituent variations enhance both the structural and biological properties of the eugenol derivatives, offering critical perspectives on how their molecular structure dictates activity, thereby validating their future utility as promising antidiabetic drug candidates.

Keywords: α-amylase binding affinity, epoxide ring-opening, sonochemical synthesis, structure-activity relationship, substituent electronic effect.