ABSTRACT Neutral sphingomyelinase 2 (nSMase2) plays a pivotal role in exosome biogenesis and the progression of several neurodegenerative disorders and cancers. In this study, a series of hexahydropyrimidine and tetrahydropyrimidine derivatives were synthesized to explore their potential as nSMase2 inhibitors. The compounds were evaluated for Bacillus cereus SMase inhibition, which shares a highly conserved substrate‐binding site with human nSMase2. The hexahydropyrimidine derivatives exhibited superior activity, with 4‐(4‐fluorophenyl)‐6‐oxo‐2‐thioxohexahydropyrimidine‐5‐carbonitrile (compound 1j , IC 50 = 1.88 μM) emerging as the most potent inhibitor fourfold more active than the reference compound Cambinol (IC 50 = 7.49 μM). Compound 1j also demonstrated metal‐chelating ability with Fe 3+ and Cu 2+ ions, which are implicated in the pathology of these diseases. Molecular docking studies revealed favorable interactions with the B. cereus SMase structure, and in silico ADME profiling suggested drug‐like properties. These findings highlight novel hexahydropyrimidine derivatives as promising nSMase2 inhibitors for further investigation.
Öztürk et al. (Sun,) studied this question.