Multifunctional Mercapto-tacrine Derivatives for Treatment of Age-Related Neurodegenerative Diseases

Abstract

Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules for the therapy of age-related neurodegenerative diseases.

New Tacrine Hybrids with Natural‐Based Cysteine Derivatives as Multitargeted Drugs for Potential Treatment of Alzheimer's Disease

“…The antioxidant activity measured herein for SAC and SPRC is quite low, although they have recognized in vitro neuroprotective activity (33); this may be associated with an increased antioxidant capacity inside the cells due to enzymatic deprotection of the sulphhydryl group, similar to the intracellular glutathione, the major antioxidant in nerve cells (34). Therefore, for the tacrine-organosulfur cysteine hybrids herein studied, identical neuroprotective activity inside the cell is also expected, as otherwise recently reported for other tacrine-mercapto derivatives (35).…”

Multifunctional tacrine–trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties

“…4B that the compound do not lead to cell death at concentration ranging from 1.563 to 12.5 mM. After studying the previous reports [24,42], we found that, in fact, similar phenomena were also observed in reported compounds and marketed drugs (e.g., mercapro-tacrine derivatives, galanthamine and donepezil). The increased cell death at high concentration might arise from additional interactions between compound and other biological targets.…”

“…To determine whether introduction of trolox could reduce hepatotoxicity, compound 6d was selected for the assay with male rats [24,43]. After treating rats with highest tolerated dose of tacrine (6 mmol/100 g body weight) or equimolar dose of 6d, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum obtained at different times (0, 24, 36 and 72 h) were measured.…”

“…The retained best poses were visually inspected and the interactions with binding pocket residues were analyzed. [24,43]. Rats were housed in a room that was automatically maintained on a 12-h light/dark cycle at 25 C and proper humidity.…”

“…Therefore, given all the above facts, researchers hypothesized that combining tacrine with an antioxidant fragment might afford more effective multifunctional molecules, which could not only inhibit AChE and reduce the hepatotoxicity of tacrine but also exhibit neuroprotective effect by decreasing the oxidant damage in brain. To test this hypothesis, some tacrineeantioxidant hybrids have been synthesized such as tacrineesilibinin hybrid [22], tacrineeferulic acid hybrid [23] and mercaptoetacrine hybrids [24]. All these compounds showed improved pharmacological properties and low hepatotoxicity compared to tacrine.…”