Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the elderly inviduals, with a prevalence twice as high in the female population. [1] Acetylcholine inhibitors (AChEIs) are one of the most investigated class of chemical compounds in treatment of AD. As a part of our ongoing research in AChEIs development, we designed and synthesized four novel compounds (4a-d) that contain tacrine moiety as AChE pharmacophore. Tacrine derivatives are particularly interesting in this area of research, due to the high inhibitory activity towards AChE. New compounds were synthesised according to the Scheme 1. The diamino tacrine derivatives 1a-d were obtained by SNAr of 9-chloro-1,2,3,4 tetrahydroacridine with appropriate diamine, while 4-methylacetophenone condensation with CS2 produced α-aroylketene dithioacetals 2. [2] N-substitution of dithioacetals 2 with diamine 1, provided N,S acetals 3 a-d which were converted into final compounds 4a-d by cyclocondensation with hydrazine [3] in high yields (50-72%). Scheme 1. Reagents and conditions: (i) PhMe, reflux, 28-71 h; (ii) N2H4 ·H2O, EtOH, reflux, 45-96 h.All newly synthesized compounds were evaluated for their inhibitor activity toward eeAChE by Elman's in vitro spectrophotometric method modified for 96 well. All tested compound shown high inhibitory activity with IC50 values ranging from 313-430 nM, making them promising lead compounds for further development of new drug candidates. References:[1] J.L. Podcasy, et al,. Dialogues Clin Neurosci. 18 (2016) 437-446.[2] P. Dhanalakshm ,et al., RSC Adv. 4 (2014) 12028-12036.[3] S. Kuettel, et al, J. Med.Chem. 50 (2007) 5833-5839.