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

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. [ABSTRACT FROM AUTHOR]