Multifunctional hydroquinone-1,2,3-triazole hybrids: Synthesis, biological evaluation, molecular docking, ADMET profiling, and in silico mechanistic insights as potential therapeutic agents

In response to the need for multi-target agents for complex diseases, two novel series of hydroquinone-1,2,3-triazole hybrids (5a-e and 6a-e) were synthesized to investigate their multifunctional therapeutic potential and establish clear structure-activity relationships (SAR). Biological evaluations revealed distinct and potent activities, with SAR analysis identifying exceptional lead compounds based on their molecular scaffold. The biological results highlighted a clear divergence in scaffold preference. The mono-adduct scaffold of Series 5 was found to be crucial for Anticancer activity, with compound 5a exhibiting strong antiproliferative effects against Caco-2 cells (IC₅₀ = 0.69 μM) and a high selectivity index of 26.12, outperforming Methotrexate. Conversely, the bis-adduct scaffold of Series 6 was optimal for cholinesterase inhibition. The fluoro-substituted 6d showed potent dual inhibitory activity (AChE IC₅₀ = 1.18 μM; BuChE IC₅₀ = 2.34 μM), superior to standard drugs. Additionally, compound 6b was identified as a notable antioxidant, with a molar potency in the ABTS assay approximately 3.2-fold greater than that of ascorbic acid. In silico studies provided a robust mechanistic rationale for these findings. Molecular docking revealed that 6d achieves its high potency by binding to both the Catalytic (CAS) and Peripheral Anionic (PAS) sites of AChE through key interactions, including a critical halogen bond. ADMET predictions further distinguished the therapeutic profiles, identifying the BBB-permeable Series 5 for potential CNS applications and the non-permeable Series 6 for peripheral targets. Overall, this study validates the hydroquinone-triazole scaffold for creating potent multi-target agents, with 5a and 6d emerging as highly promising leads for Anticancer and neurodegenerative therapies, respectively, warranting further preclinical evaluation.

Anticancer activity; Antioxidant activity; Cholinesterase inhibition; Hydroquinone; In silico; SAR; Triazole.