Synthesis, Characterization, and In Silico Investigation of Novel Bicyclic Benzylidene Thiazolo[3,2-a]Pyrimidin-3(2H)-one Derivatives

Thiazolopyrimidines and their derivatives have diverse pharmacological uses. This study aimed to synthesize four new bicyclic benzylidene thiazolo[3,2-a]pyrimidin-3(2H)-one derivatives (7a–d), with yields ranging from 89%–94%. The compounds were analyzed using FT-IR, ¹H NMR, and ¹³C NMR. In silico molecular docking assessed their interactions with Nicastrin (PDB ID: 7Y5X) and Lp-PLA2 (PDB ID: 5JAN–4), showing high polarity and flexibility, but some limitations in unsaturation, lipophilicity, size, and solubility. The BOILED-Egg method indicated that while these compounds cannot cross the blood-brain barrier, they can be absorbed via the gastrointestinal tract. Online predictions suggest they may have biological activity, with an LD₅₀ of 2000 mg/kg and a Toxicity Class 4 rating. Molecular docking showed Compound 7c had the highest binding affinity to Nicastrin (XP GScore = −10.780) and the most stable binding through hydrophobic interactions (LipophilicEvdw = −7.293), while Compound 7d had the strongest binding to Lp-PLA2 (XP GScore = −7.578) with π-π stacking interactions at A:PHE698. Stability was confirmed in simulations, with both protein-ligand complexes maintaining stability over time. The pharmacokinetics and properties of these compounds suggest potential as inhibitors of Nicastrin and Lp-PLA2, making them promising candidates for future therapeutic development.