Synthesis of Tacrine Analogues and Their Structure-Activity Relationships

Abstract

Three man synthetic routes to analogues of tacrine are described: reaction of anthranilonitriles with cyclohexanone and other ketones, reaction of various anilines with alpha-cyanoketones, and reactions involving anilines and cyclic beta-ketoesters. Although tacrine has a wide range of pharmacological effects, it is best known as an inhibitor of cholinesterase enzymes. Many of the analogues that have been made have not been tested against acetylcholinesterase or butyrylcholinesterase activity. Consequently, there is limited information from which a detailed understanding of structure-activity relationships can be derived. However, some halogenated derivatives are not only more potent acetylcholinesterase inhibitors than tacrine, they are also more selective for acetylcholinesterase than for butyrylcholinesterase.

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

“…30,[33][34][35] In Figure 1, we showed the regions of the structure of THA that can be modified by bioisosterism strategy. 3 The quinoline nucleus present in (a) is the pharmacophore group in THA.…”

“…31,32 Therefore, many efforts have been made for the synthesis of new tacrine analogues, with only a few dealing with the synthesis of chiral THA derivatives, although they showed important pharmacological activities. 30,[33][34][35] In Figure 1, we showed the regions of the structure of THA that can be modified by bioisosterism strategy. 3 The quinoline nucleus present in (a) is the pharmacophore group in THA.…”

Synthesis of α-oxycarbanilinophosphonates and their anticholinesterase activities: the most potent derivative is bound to the peripheral site of acetylcholinesterase

“…Acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) and is the most widely used target enzyme in studies with the purpose to synthesize new and more effective therapeutic agents to treat patients with diseases such as Alzheimer's disease (AD) or myasthenia gravis [7][8][9] . Reversible inhibition of brain AChE by anti-AD drugs such as tacrine 10 , donepezil 11 , and huperzine 12 increases the ACh levels and improves neurotransmission in cholinergic synapses 13 . AChE is also used widely as a target in the studies of compounds with insecticidal activities, as all commercially available organophosphate compounds are believed to exert their effects through potent reversible or irreversible inhibition of this enzyme 14 .…”

“…The other binding site is peripheral anionic site (PAS) which spans from residue W286, at the mouth of the gorge, to D74, at the boundary between PAS and A-Site 15,16 . Inhibitors of AChE bind to A-site (organophosphates 14 , rivastigmine 17 , tacrine 10 ) or PAS (propidium 18 ) or to both of them (donepezil 11 ) in AChE.…”

Understanding Acetylcholinesterase Inhibitors: Computational Modeling Approaches

“…66,88 It is a derivative of acridine synthesized in 1945, applied first as an antimicrobial agent and monoamine oxidase inhibitor. 89,90 THA is a reversible inhibitor, non-competitive and non-selective for AChE. In patients with good tolerance to it, this drug increases moderately the cognitive function but, has high hepatotoxicity and high incidence of side effects 66 Although tacrine is not first drug of choice, it is taken as reference in search of more potent AChEIs.…”