The first-in-class 1,3,5-triazine-derived dual 5-HT6R/FAAH modulators in search for potential drug against neurodegenerative diseases with cognitive impairment.

Due to complex etiology, a promising approach to find an effective therapy of Alzheimer's disease (AD) lies in the search for multitarget ligands. Within this study, we have identified novel 1,3,5-triazine derivatives that modulate either the serotonin 5-HT6 receptor and the fatty acid amide hydrolase (FAAH) enzyme, also slightly inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) enzymes, thus representing pioneering multitarget approach to address key pathological mechanisms in AD. Among the synthesized compounds, the m-chlorobenzyl- 7 (5-HT6R pKi = 7.59) and the trimethoxybenzyl- 23 (5-HT6R pKi = 6.33) derivatives exhibited the most favorable multitarget action, with 5-HT6R selectivity over other GPCR off-targets. Comprehensive molecular modeling provided insights into the compounds interactions with the molecular targets considered. In vitro evaluations revealed satisfactory metabolic stability and low risks of toxicity, including neurotoxicity. Notably, 23 demonstrated significant neuroprotective effects against Aβ1-42-induced toxicity in hippocampal model (HT-22). Furthermore, in a Novel Object Recognition (NOR) test, both 7 and 23 ameliorated MK-801-induced memory deficits in rats. The results indicate the therapeutic potential for these first-in-class dual modulators of both, endocannabinoid system and serotonergic neurotransmission, to address neurodegenerative diseases such as AD.