Synthesis, biological evaluation and molecular docking studies of novel 2-alkylthiopyrimidino-tacrines as anticholinesterase agents and their DFT calculations

To search for effective and selective inhibitors of cholinesterases (AChE and BuChE), a series of poly-functionalized Tacrine-derived compounds specifically 2-(alkylthio)-4-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-5-amines were designed an synthesized via Friedlander reaction. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data (1H NMR, 13C NMR) and elemental analyses (CHNS). Compounds 3a-h were evaluated for their abilities to inhibit AChE and BChE. The obtained biological results revealed that some synthesized compounds displayed higher anti-cholinesterase activity in comparison to Galantamine. Among them, compound 3d bearing S-ethyl and 4-chlorophenyl moieties showed the most potent activity against AChE/BuChE with IC50s values of 4,32 and 15,10 μM, respectively. The anti-AChE activity of 3d was 5-fold more than that of reference drug Galantamine. Moreover, molecular docking studies were performed for the most active derivatives, 3d and 3c, in which binding mode between these compounds and the receptors were determined. Density functional theory (DFT) method at B3LYP/6–311++G (d,p) level of theory was employed to gain insights into the molecular structure of the target compounds. Molecular electrostatic potential (MEP) mapping, reactivity indices such as electronegativity, electrophilic index, softness and hardness as well as frontier molecular orbitals HOMO-LUMO have been investigated for 3a-3c as representative compounds. In addition, their antiradical activity has been predicted by computing bond dissociation enthalpies (BDEs). [Display omitted] •Synthesis of new, AChE inhibitors containing Tacrine and thiopyrimidine moieties•Their inhibitory activities against ChE were investigated and IC50 values of inhibitor compounds were determined.•All compounds showed activities comparable to or significantly higher than Galantamine.•In silico physicochemical characters assessing and DFT calculations proved compounds as promising leads.•Density functional theory (DFT) method was employed to gain insights into the molecular structure of the target compounds.