Targeting Alzheimer's disease with novel dual-function 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives

In the field of medicinal chemistry, the versatility of the thiosemicarbazone scaffold makes it a promising platform for the development of next-generation pharmaceuticals. In this paper the thiosemicarbazone scaffold was explored to obtain novel series of derivatives: a) thiosemicarbazones 15-31, and 33 containing a linear thiosemicarbazone scaffold, b) 34-38 and 44-64 containing pyrazoline ring, and c) 39-43 containing the dihydropyrimidine cycle. Among these, compounds 21 , 23 , 26 , 33-35, 37 , 38 , 44 , 57 , 61 , and 62 demonstrated no significant cytotoxic effects on HDFa cells at concentrations up to 500 mu g/mL. Importantly, compounds 21 , 23 , 26 , 33 , 34 , 35 , and 37 exhibited significant protective effects against neurotoxicity induced by beta-amyloid peptide (1-42) in differentiated SHSY-5Y cell cultures. Enzymatic assays targeting BACE1 and AChE revealed modest inhibitory activity in compounds 21 , 23 , and 34 , 37 , respectively. The identification of compounds with inhibitory effects and neuroprotective activity against beta-amyloid peptide (1-42) offers a platform for further optimization and refinement of these compounds to enhance their potency and selectivity.