Designing multi-targeted drugs (MTD) for Alzheimer's disease (AD) is now one of the priorities for medicinal chemists, as the disease has a complicated not fully understood pathological nature and the approved mono-targeted drugs only alleviate the symptoms. In this study, the synthesis, spectral analyses and in vitro inhibition activity against cholinesterase (ChE) and monoamine oxidase (MAO) enzymes of a novel series of N-[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-2-(4-un/substituted) cyclic secondary amino-acetamide/propanamide derivatives were done. Generally, derivatives were more selective against acetylcholinesterase (AChE) and h-MAO-B than butyrylcholinesterase (BChE) and h-MAO-A, respectively. Derivatives 4a, 4b, 3a, 3d and 3b ordered from the most potent to the least displayed significant inhibition against AChE. Also, derivatives 4a, 4b and 3a still maintained their significant inhibition against h-MAO-B in the same potency order, making them dual inhibitors and MTD candidates for AD. Binding interactions with several crucial amino acid residues for activity and selectivity as well as the stability of the most active derivatives-enzyme complex were confirmed utilizing molecular docking and molecular dynamic simulation studies.Communicated by Ramaswamy H. Sarma.

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC₅₀ values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.