Novel Hexahydropyrimidine Derivatives as Potential Neutral Sphingomyelinase 2 Inhibitors: Synthesis, Metal Chelation,...

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, IC₅₀ = 1.88 μM) emerging as the most potent inhibitor fourfold more active than the reference compound Cambinol (IC₅₀ = 7.49 μM). Compound 1j also demonstrated metal-chelating ability with Fe³⁺ and Cu²⁺ 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.