Conjugates of tacrine and 1,2,4-thiadiazole derivatives as new potential multifunctional agents for Alzheimer’s disease treatment: Synthesis, quantum-chemical characterization, molecular docking, and biological evaluation

New Hybrids of 4-Amino-2,3-polymethylene-quinoline and p-Tolylsulfonamide as Dual Inhibitors of Acetyl- and Butyrylcholinesterase and Potential Multifunctional Agents for Alzheimer’s Disease Treatment

“…As was observed earlier for other dual binding site AChE inhibitors with lengthy spacers [49,50,[81][82][83][84], they are located inside the AChE gorge in an elongated conformation whereas they are bent inside the wider BChE gorge. Consequently, an increase in the spacer length for conjugates with the same ring size leads to better occupation of the AChE PAS by the p-tolylsulfonamide fragment.…”

“…The differential interaction of bulky inhibitors with AChE and BChE is highly dependent on the difference in structure of the active site gorge that leads from the protein surface to the active site [49,50,[81][82][83][84]. AChE has a narrow gorge divided by the so-called bottleneck into the PAS and CAS [85,86].…”

“…A second pharmacophore is then attached via a spacer to the cholinesterase inhibitor [40][41][42][43][44]. Such hybrid molecules expand the range of pharmacological activities of a parent anticholinesterase compound by adding antiaggregant, antioxidant, and other desirable properties [45][46][47][48][49][50].…”

Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System

“…There were additional binding poses of AA-CHOL outside the active site, which was consistent with a mixed-type inhibition observed experimentally. Arachidonic chain was found bent in the lower part of the gorge; such difference in the binding mode of ligands with lengthy chains to AChE and BChE is quite typical due to the difference of the gorge radii [30,31].…”

“…There were additional binding poses of AA-CHOL outside the active site, which was consistent with a mixed-type inhibition observed experimentally. Arachidonic chain was found bent in the lower part of the gorge; such difference in the binding mode of ligands with lengthy chains to AChE and BChE is quite typical due to the difference of the gorge radii [30,31]. According to the molecular docking results, choline moiety of AA-CHOL was found in the AChE active site, binding to the cation-binding pocket, but carbonyl oxygen atom of the ester group was outside the oxyanion hole due to a large size of acyl chain, which makes hydrolysis reaction unlikely ( Figure 7A).…”