Quinazoline derivatives as novel bacterial sphingomyelinase enzyme inhibitors

Ozturk O. K., Oyardı Ö., Dündar Y.

Bioorganic Chemistry, cilt.154, 2025 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 154
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.bioorg.2024.108079
  • Dergi Adı: Bioorganic Chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Veterinary Science Database
  • Anahtar Kelimeler: Anti-hemolytic activity, Antibacterial activity, Bacillus cereus sphingomyelinase, Cholinesterase, Metal chelation, Molecular docking, Quinazoline
  • Gazi Üniversitesi Adresli: Evet

Özet

Bacillus cereus sphingomyelinase C (B. cereus SMase), which plays a crucial role in bacterial virulence, has emerged as a new therapeutic target for treating opportunistic infections caused by this pathogen. It also shares catalytic domain similarity with human neutral sphingomyelinase 2 (nSMase2), which is implicated in Alzheimer's disease. In this study, a series of quinazoline derivatives were synthesized and evaluated for their inhibition of B. cereus SMase, electric eel acetylcholinesterase (EeAChE), and equine butyrylcholinesterase (eqBuChE). Moreover, the antibacterial, anti-hemolytic and metal chelation properties of the selected compounds were determined. Among the synthesized compounds, 6-chloro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (compound 4) and 6-fluoro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (compound 5) exhibited promising inhibition of B. cereus SMase, with IC50 values of 6.43 and 6.50 µM, respectively. The mode of inhibition of compound 4 was determined as mixed-type inhibition by enzyme kinetic study. In addition, compounds 4 and 5 showed 59.50% and 51.66% eqBuChE inhibition at 50 µM concentration, respectively. Furthermore, compound 4 reduced B. cereus-induced hemolysis on sheep erythrocytes and able to form a complex with Cu2+ in ligand:metal ratio of 2:1. Additionally, cambinol, an inhibitor of both nSMase2 and B. cereus SMase, was found to exhibit inhibitory activity against eqBuChE, with IC50 value of 7.40 µM. The biological data were also supported by the results of molecular docking studies and in-silico physicochemical properties/ADME predictions of the selected compounds were determined.