Makhaeva_2024_Molecules_29_321

Reference

Title : Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease - Makhaeva_2024_Molecules_29_321
Author(s) : Makhaeva GF , Kovaleva NV , Rudakova EV , Boltneva NP , Lushchekina SV , Astakhova TY , Timokhina EN , Serkov IV , Proshin AN , Soldatova YV , Poletaeva DA , Faingold, II , Mumyatova VA , Terentiev AA , Radchenko EV , Palyulin VA , Bachurin SO , Richardson RJ
Ref : Molecules , 29 :321 , 2024
Abstract :

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, the most active was 17d IC(50) 15.1 +/- 0.2 nM) and butyrylcholinesterase (BChE, the most active was 18d: IC(50) 5.96 +/- 0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated the potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced beta-amyloid (Abeta) aggregation. Hybrids also exhibited the inhibition of Abeta self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as the inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability, suggesting the CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for the potential treatment of AD.

PubMedSearch : Makhaeva_2024_Molecules_29_321
PubMedID: 38257233

Citations formats

Makhaeva GF, Kovaleva NV, Rudakova EV, Boltneva NP, Lushchekina SV, Astakhova TY, Timokhina EN, Serkov IV, Proshin AN, Soldatova YV, Poletaeva DA, Faingold, II, Mumyatova VA, Terentiev AA, Radchenko EV, Palyulin VA, Bachurin SO, Richardson RJ (2024)
Combining Experimental and Computational Methods to Produce Conjugates of Anticholinesterase and Antioxidant Pharmacophores with Linker Chemistries Affecting Biological Activities Related to Treatment of Alzheimer's Disease
Molecules 29 :321

Makhaeva GF, Kovaleva NV, Rudakova EV, Boltneva NP, Lushchekina SV, Astakhova TY, Timokhina EN, Serkov IV, Proshin AN, Soldatova YV, Poletaeva DA, Faingold, II, Mumyatova VA, Terentiev AA, Radchenko EV, Palyulin VA, Bachurin SO, Richardson RJ (2024)
Molecules 29 :321