Work

Novel Hexahydropyrimidine Derivatives as Potential Neutral Sphingomyelinase 2 Inhibitors: Synthesis, Metal Chelation, and In Silico Studies

Year: 2026

Type: article

Abstract: 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.

Source: Chemical Biology & Drug Design

DOI: 10.1111/cbdd.70245

Authors: Ozge Kuyrukcu Ozturk, Yasemin Dundar

Institution: Gazi University

Language: English

Topic: Sphingolipid Metabolism and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funder: Türkiye Bilimsel ve Teknolojik Araştırma Kurumu