[1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazin-3-Yl)methyl)pyrimidin-4(3H)-One Derivatives as New Therapeutic Candidates as COX-II Inhibitors: Green Synthetic Approach and In Silico Studies

This study presented a systematic synthesis of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)methyl)-6-methylpyrimidin-4(3H)-one derivative (9a-j) through three distinct methodologies: a traditional multistep approach, a two-step solid-phase synthesis, and a one-step green synthesis. The green synthesis demonstrated superior atom economy, minimal impurities, and adherence to sustainability principles. The synthesized compounds were evaluated for cyclooxygenase (COX) inhibition, with 9e showing the highest COX-II selectivity (SI = 17.10), supported by in vitro and in silico analyses. Structure–activity relationships revealed the impact of electron-withdrawing groups on binding affinity. This work highlighted an efficient, environmentally conscious approach to creating pharmacologically relevant heterocycles.