a b s t r a c tA novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC 50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH 4 OAc, using InCl 3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE.

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Cholinesterase enzymes are important targets for the therapy of Alzheimer's disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo-and heterodimers of bis (7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl 3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo-and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds. Keywords: bistacrine, chiral, cholinesterases, synthesis, molecular docking IntroductionAlzheimer's disease (AD) is one of the leading causes of death among elderly people in the World, and its treatment remains a challenge for the pharmaceutical community. Nearly a million new cases per year it is expected to emerge by 2050.1,2 The proposed cholinergic hypothesis of cognitive impairment has been accepted for decades to explain AD and is characterized by the loss of cholinergic basal forebrain, and their projections to the cerebral cortices. 2,3 According to this hypothesis, the memory and cognitive decline well-marked in AD result from a deficit of the important neurotransmitter acetylcholine (ACh). In this context, the inhibition of cholinesterase enzymes (ChEs) that are responsible for the hydrolyses of ACh emerge as a symptomatic treatment to relieve these symptoms. [4][5][6] The current therapeutic options for AD are limited to three inhibitors of acetylcholinesterase (AChEI):4-8 donepezil (Aricept ® ), rivastigmine (Exelon ® ) and galantamine (Razadyne ® , Reminyl ® ). In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.The cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes which are found in the central nervous system (CNS) and catalyze the hydrolysis of ACh efficiently but at different rates. [9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring Lopes et al. 2219 Vol. 28, No. 11, 2017 approximately 20 Å in length. It is formed by a catalytic anionic site (CAS) composed by the catalytic triad Ser200, His440 and Gl...

A series of selective butyrylcholinesterase inhibitors were obtained. The absence of in vitro cytotoxicity and good ADME-Tox profile make these compounds new promising prototypes for the treatment of Alzheimer's disease.

In the context of the search for multitarget drugs with improved efficacy against neurodegenerative disorders, carbohydrate derivatives have emerged as promising candidates for Alzheimer's therapy. Herein we describe the synthesis...

New photoactive molecular hybrids containing both lophine and pyrimidine moieties as optical sensors.

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