2. Academic Validation
  3. Discovery of a novel pyrido[1,2-a]thiazolo[5,4-d]pyrimidinone derivatives with excellent potency against acetylcholinesterase

Discovery of a novel pyrido[1,2-a]thiazolo[5,4-d]pyrimidinone derivatives with excellent potency against acetylcholinesterase

  • Mol Divers. 2024 Jun 27. doi: 10.1007/s11030-024-10920-x.
Yan Zeng 1 2,  Zhifeng Chen 1,  Zhiyong Yang 1,  Fangxue Yuan 1,  Lifei Nie 3,  Chao Niu 4 5
Affiliations

Affiliations

  • 1 Xinjiang Key Laboratory of Coal Mine Disaster Intelligent Prevention and Emergency Response, Xinjiang Institute of Engineering, Urumqi, 830023, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China. nielf@ms.xjb.ac.cn.
  • 4 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China. niuchao@ms.xjb.ac.cn.
  • 5 University of Chinese Academy of Sciences, Beijing, 100049, China. niuchao@ms.xjb.ac.cn.
PMID: 38935303 DOI: 10.1007/s11030-024-10920-x
Abstract

As mimetic compounds of the natural alkaloid mackinazolinone, forty pyrido[1,2-a]thiazolo[5,4-d] pyrimidinone were designed and synthesized from a bioisosterism approach. The structure of these compounds was confirmed through analysis using 1H NMR, 13C NMR, and HRMS techniques. All the compounds were evaluated for their anticholinesterase activities and cytotoxicity on normal cells (293 T) by the Ellman method and methyl thiazolyl tetrazolium (MTT) method in vitro. and the structure-activity relationships (SARs) were summarized. The results showed that most of the compounds effectively inhibited acetylcholinesterase (AChE) in the micromolar range with weak cytotoxicity. Compound 7o exhibited the best inhibitory activity against AChE, displaying an IC50 values of 1.67 ± 0.09 µM and an inhibitory constant Ki of 11.31 µM as a competitive inhibitor to AChE. Molecular docking indicated that compound 7o may bind to AChE via hydrogen bond and π-π stacking. Further molecular dynamics (MD) simulations indicated a relatively low binding free energy (- 27.91 kJ·mol-1) of compound 7o with AChE. In summary, the collective findings suggested that 7o was promising as a potential novel drug candidate worthy of further investigation for the treatment of Alzheimer's disease.

Keywords

Acetylcholinesterase; Bioisosterism; Molecular docking; Molecular dynamics; Thiazolo[5,4-d]pyrimidinone.

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