Design, Synthesis, and Molecular‐modeling Study of Aminothienopyridine Analogues of Tacrine for Alzheimer's Disease

Abstract

2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results.

Recent advances in the chemistry of thieno[2,3-b]pyridines 1. Methods of synthesis of thieno[2,3-b]pyridines

“…The Friedländer synthesis was used to obtain thienopyridines 84, the structural analogs of tacrine 85, which are acetylcholinesterase inhibitors (Scheme 35). [156][157][158][159][160][161] The search for new compounds in this series is due to the fact that tacrine, being one of the few drugs effi cient in the treatment and therapy of Alzheimer´s disease, has a pronounced hepatotoxic eff ect. 162 The reaction of ketones with 2-amino-3-cyanothiophenes is usually catalyzed by acids: TsOH and AlCl 3 , The Friedländer reaction takes place under a wide variety of conditions.…”

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

“…Thioflavin-and deferiprone-based molecules acted as AChE inhibitors and dissociated toxic A␤ aggregates [116]. Sym-triazines and 1,4-substituted 4-(1H)pyridylene-hydrazones inhibited A␤ fibril formation and AChE [117][118][119], as did tacrine-benzothiazole hybrids [120] and novel tacrine analogs [121,122]. Rhein-huprine hybrids showed AChE and BChE inhibiting properties and BACE1, dual A␤ 42 , and tau anti-aggregating activities [123].…”

Cognitive Enhancers in Moderate to Severe Alzheimer's Disease

“…Some of them are derived from a natural plant constituent, cardenol. 99 Various others represent derivatives of tacrine, [100][101][102][103] despite the known hepatotoxicity of the parent compound. In two series, toxicity was reduced by using 7-methoxytacrine as a core compound.…”