Pharmacological Investigations of Selected Multitarget-Direct Ligands for the Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a complex, degenerative condition linked to memory loss and cognitive degradation. The phenyl sulfonyl-pyrimidine derivatives containing dimethoxy-chloro substituent (BS-10 and BS-22) were previously recognized as multitarget-directed ligands (MTDLs) due to their ability to inhibit acetylcholinesterase (AChE) at low nanomolar concentrations (IC50=47.33±0.02 and 51.36±0.04 nM respectively) while also reducing amyloid beta (Aβ) aggregation. In the current investigation, we investigated the in vivo and ex-vivo effects of BS-10 and BS-22 chemicals on cognition and the cholinergic system. We have used scopolamine and Aβ1-42 models of cognitive impairment which were measured during Y-maze and passive avoidance apparatus. Results showed that BS-10 at 10 mg/kg compared to BS-22 at 20 mg/kg rescued memory impairment more significantly. Moreover, ex-vivo and biochemical studies exhibited both compounds improved the hippocampal acetylcholine (Ach) level by reducing AChE activity as well as antioxidant properties. In addition, BS-10 and BS-22 attenuated Aβ1-42 induced cognitive deficiency in rats during Y-maze tests and significantly restored mitochondrial membrane potential and reduced the tau protein level in rats (p<0.05). In summary, our results indicated that MTDLs BS-10 and BS-22 would be a promising therapeutic approach in AD. © 2022 Wiley-VCH GmbH.