Synthesis and evaluation of tacrine-related compounds for the treatment of Alzheimer's disease

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies

“…Of note, as previously reported for some tacrine-related dimeric compounds [31], the new hybrids herein described have the ability to retain molecules of water, which cannot be removed after drying the analytical samples under the aforementioned standard conditions. Thus, the elemental analyses of these compounds showed the presence of variable amounts of water, which have been indicated in the corresponding compound formulas.…”

How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

“…The synthesis, in vitro pharmacology and molecular modeling of a series of tacrine±huperzine A hybrids (huprines; Fig. 1) as AChE inhibitors have been reported recently [11,12,13]. The most potent compound has an inhibition constant (K I ) for human AChE of 26 pM, which means an anity around 1200 times higher than that of tacrine [14,15], making these compounds valuable candidates for the palliative treatment of Alzheimer's disease.…”

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

“…Worthy of note, as previously observed, 16 only the shown aminoquinolines, having the heterocyclic ring and the endocyclic C-C double bond in an anti-arrangement, were observed. This fact may be explained taking into account the mechanism of this reaction, which is illustrated in Scheme 2 for the reaction of enone 13a and o-aminobenzonitrile (14). Reaction of 13a and 14 would give imine 32 which would be in equilibrium with two regioisomeric enamines (33 and 34), the antienamine 33 being reasonably the thermodynamically more stable, as is the case for the anti-enamine 37, obtained by reaction of ketone 36 with pyrrolidine (Scheme 3).…”

“…Some huperzine A derivatives (5 and 6) more potent than the natural product were also developed by modeling the interaction of huperzine A 12 (7) with AChE. 13 Some time ago, we carried out the synthesis and evaluation of several THArelated AChE inhibitors such as 4, 14 formally derived from THA by molecular duplication. Moreover, some new THA-based compounds, containing two THA subunits with their amino groups connected by an oligomethylene chain, such as 8, were designed taking into account the existence of two binding sites for THA in AChE.…”