Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Abstract

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...

Molecular Targets of Bis (7)-Cognitin and Its Relevance in Neurological Disorders: A Systematic Review

“…Tacrine (9-amino-1,2,3,4-tetrahydroacridine, under the trade name Cognex®, was the first drug approved for the treatment of AD in 1993 (Han et al, 2012). Other AChE inhibitors, such as donepezil (Aricept®), rivastigmine (Exelon®) and galantamine (Reminyl®) introduced in 1996, 2000, and 2001, respectively, in addition to the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda®) followed the release of tacrine (Han et al, 2012; Lopes et al, 2017). Tacrine binds in a reversible mode to AChE and is considered a classical AChE pharmacophore (Lopes et al, 2017).…”

“…Other AChE inhibitors, such as donepezil (Aricept®), rivastigmine (Exelon®) and galantamine (Reminyl®) introduced in 1996, 2000, and 2001, respectively, in addition to the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda®) followed the release of tacrine (Han et al, 2012; Lopes et al, 2017). Tacrine binds in a reversible mode to AChE and is considered a classical AChE pharmacophore (Lopes et al, 2017). Due to its side effects, such as hepatotoxicity and myopathy as well as its poor pharmacokinetic properties, including low bioavailability and narrow therapeutic index, a series of new tacrine-based compounds have been developed (Luo et al, 2004; Han et al, 2012).…”

“…Although the pathological processes in AD are not well-understood, it is clear that disturbances in the cholinergic system and other neurotransmitters play a pivotal role in the pathogenesis of this neurodegenerative disorder (Han et al, 2012). Strategies to develop drugs for AD have focused on acetylcholinesterase (AChE) as a target for drug design based on the cholinergic hypothesis for AD (Ros et al, 2001; Lopes et al, 2017). The cholinergic hypothesis states that increased levels of acetylcholine in the brain alleviate the cognitive deficiencies observed in AD (Ros et al, 2001).…”

Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer’s Disease

“…We evaluated the possible binding modes of the compounds in the AChE binding site through molecular docking studies. Due to significant conformational changes observed on the peripheral anionic site (PAS) [ 41 ], we selected three representative conformations of AChE following an ensemble docking strategy similar to that adopted on previous studies [ 42 , 43 , 44 ] in addition to the structure of human AChE complexed with donepezil [ 45 ] (PDB code 4EY7). The ensemble docking strategy consists in docking the compounds into each representative conformation of the receptor aiming to consider the protein flexibility [ 46 , 47 , 48 ].…”

Multifunctional properties of novel tacrine congeners: cholinesterase inhibition and cytotoxic activity

“…The multifunctional properties of tacrine derivatives, which have been discovered in recent years continue to stimulate significant interest in this field of chemistry (Anand & Singh, 2013;Čolović, Krstić, Lazarević-Pašti, Bondžić, & Vasić, 2013;Hamulakova et al, 2016;Hamulakova, Janovec, Soukup, Jun, & Kuca, 2017;Kozurkova & Kristian, 2014;Martorana et al, 2016;Melo et al, 2012;Milelli, Simone, & Ticchi, 2017;Panek, Wichur, Godyń, Pasieka, & Malawska, 2017;Proctor & Harvey, 2000;Thiratmatrakul et al, 2014;Tumiatti et al, 2010;Viayna, Sabate, & Muñoz-Torrero, 2013;Wu et al, 2017). In addition to their two basic trades concerning the inhibition of AChE/butyryl cholinesterase (AChE/BChE) and Aβ aggregation, tacrine congeners are also characterized by a variety of other features such as the ability to protect against oxidative stress, β-secretase and M 1 muscarinic receptors (Da Costa et al, 2013;Ježek, Hlaváček, & Šebestík, 2017;Kožurková et al, 2011;Lopes et al, 2017;McHardy, Wang, McCowen, & Valdez, 2017;Soukup et al, 2013;Szymański et al, 2013). Extensive overviews concerning the mode of action of these esterase systems have been the topic of several articles (Boulebd et al, 2017;Guzior, Wieckowska, Panek, & Malawska, 2015;Parveen & Kumar, 2005).…”