Synthesis and elucidation of strained galactopyronose esters as selective cyclooxygenase-2 inhibitor: a comprehensive computational approach

Abstract

Cyclooxygenase-2 (COX-2) is critically implicated in various pathologies, including inflammation, cancer, disorders involving the nervous system, and multidrug resistance. In both academic and pharmaceutical research, the development of COX-2 selective drugs as anti-inflammatory and anti-tumor therapeutics is a key focus. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) have ulcerogenic, gastrointestinal adverse effects, and myocardial infarction risk, which resulted in their limited applications. In response to this challenge, we synthesized a series of glycoconjugates featuring six-membered sugar rings and acyl chains of varying lengths attached at the C-6 position. Using molecular docking techniques, we identified galactose esters with optimal acyl chain lengths that selectively and effectively bind to the active site of COX-2 over COX-1. These compounds exhibited enhanced binding affinity and superior inhibition constants (pK_i) for COX-2, thereby offering selective inhibition with potentially reduced ulcerogenic risks, as COX-1 inhibition is thought to contribute to these side effects. The molecular docking study identified two potential compounds, G6 and G8, which were validated via MD simulation for the assessment of their stability and were compared to the complex of the standard drugs, aspirin and rofecoxib. In addition, compound structures were optimized using the DFT method under the B3LYP/6-31+g(d,p) basis set to study their physio-spectral properties, frontier molecular orbitals (HOMO–LUMO), and their energy gap that correlates to their reactivity and stability. ADMET, drug-likeness, and PASS analyses were also carried out to assess their drug-ability and toxicity profiling.