6-Acetyl-5H-thiazolo[3,2-a]pyrimidine Derivatives as the Novel Acetylcholinesterase Inhibitors: Design, Synthesis, and Biological Activity

Abstract

Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer's drugs. A series of 6-acetyl- 5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors were designed based on virtual screening methods. The target compounds which are not reported in the literature were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, 1H-NMR and 13C-NMR. The biological evaluation against human acetylcholinesterase in vitro showed most of the target compounds exhibited varying inhibition at 10 µM using the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer's disease, and a foundation in search for improved acetylcholinesterase inhibitors with the novel scaffolds. The preliminary structure-activity relationships were the 2-hydroxyethoxy group at the phenyl ring at C4 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds.

Synthesis, Characterization, and Biological Evaluation of Novel 7-Oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic Acid Derivatives

“…The bicyclic fragments were coplanar. The benzene ring C (11)…C (16) was almost perpendicular to the intramolecular bicyclic thiazolo[3,2-b]-1,2,4-triazine fragment with a θ angle of 89.584(90)°. In the meantime, the ester groups were nearly coplanar with the corresponding bicyclic fragment, and the torsion angles of S(1)-C 4 R1 = 0.0821, wR2 = 0.1780 Largest diff.…”

“…Among the various heterocycle-fused thiazole derivatives, the thiazolo[3,2-b]-1,2,4-triazinone nucleus is a crucial class of N-bridged heterocyclic compounds with a wide range of applications in the field of therapeutic chemistry. These thiazolo[3,2-b]-1,2,4-triazinone derivatives have exhibited a broad spectrum of pharmacological and biological activities, such as anticancer [12], anti-inflammatory [13], antirheumatic [14] and antiacetylcholinesterase activities [15,16], etc. Comparing thieno [2,3-d]pyrimidinone with thiazolo[3,2-b]-1,2,4-triazinone nucleus using molecular overlay method, the overlay similarity value was over 60%.…”

Antiproliferative Effect and Autophagy Inhibition of Dihydropyrimidinone‐Cinnamic Acid Hybrids

“…[6] The dihydropyrimidinic core is also found in some natural alkaloids (batzelladines) extracted from marine sponges such as Batzella sp., those compounds are known by the biological importance such as anti-human immunodeficiency virus (HIV) activity. [7] DHPMs are known for having several other biological activities such as acetylcholinesterase inhibition, [8,9] antioxidant activity, [10][11][12] microsomal prostaglandin E synthase-1 (mPGES-1) inhibition [13] and other relevant activities. [14,15] Monastrol is a small molecule that selectively inhibits the mitotic kinesin Eg5, a critical motor enzyme that is required for the correct bipolar formation of the mitotic spindle.…”

Ultrasound-Assisted Green Syntheses of Novel Pyrimidine Derivatives and Their Comparison With Conventional Methods

“…As a result of ongoing research in the series of substituted pyrimidines, new compounds have been discovered that have antibacterial and antimicrobial [1][2][3][4], antifungal [5,6], antitumor [7][8][9], anti-inflammatory [10,11], anticonvulsant [12,13], antioxidant [14,15], antiviral [16,17], anti-HIV [18][19][20], anti-tuberculosis [21,22], antimalarial [23][24][25], cardiotonic [26,27] activity. Some pyrimidine derivatives were inhibitors of acetylcholinesterase [28,29].…”