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

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 K_i 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.

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