1620645-77-3Relevant academic research and scientific papers
Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine “bio-oxidizable” prodrugs: Synthesis, biological evaluation and structure-activity relationship
Azzouz, Rabah,Peauger, Ludovic,Gembus, Vincent,??n?a?, Mihaela-Liliana,Papamica?l, Cyril,Levacher, Vincent,Sopková-de Oliveira Santos, Jana
, p. 165 - 190 (2018/04/21)
As an extension of our previous work on donepezil-based “bio-oxidizable” prodrug approach, two new classes of N-benzylpyridinium donepezil analogues in tetralone B2 and acetophenone B3 series and a new set of indanone derivatives B1 were investigated along with the corresponding dihydropyridine prodrugs A1-3. A total of fifty one N-benzylpyridinium quaternary donepezil analogues B1-3 and twenty two prodrugs A1-3 were synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC50 > 10 μM), a large number of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC50 = 0.36 nM). In addition, in silico docking studies were conducted for several compounds to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four separated isomers of prodrug 23h (IC50 ranging from 173 nM to 10 μM) but also significant variations of the oxidation rate between two separated diastereoisomers of prodrug 24a. This work provides useful information in the search of a preclinical candidate to conduct further development of this attractive “bio-oxidizable” prodrug strategy.
OXIDISABLE PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE AS ANTI-ALZHEIMER AGENTS
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Page/Page column 103; 104; 105; 106, (2014/08/07)
A compound of formula (I) in which the dotted lines indicate the presence of at least one double bond; n = 0 to 4; R3 and R4 are H, or when n = 1, R3 and R4 can also form together a double bond between the carbon atoms, and m = 0, 1 or 2, Z is CH or N or Z is C and - CHR3- is =CH- linked by the double bond to cyclopentanone; or - (-)m- is absent, and Z is NH, >N-alkyl, >N-phenyl, >N-benzyl or >N heteroaryl; R8 is alkyl, aryl or heteroaryl which can be optionally substituted; EWG represents an electron withdrawing group selected from the group comprising COOR, COSR, CONRR', CN, COR, CF3, SOR, SO2R, SONRR', SO2NRR', NO2, halogen, heteroaryl; and the pharmaceutical salts and stereisomers thereof. The compounds of formula (I) are potent in the treatment of neurodegenerative diseases such as Alzheimer's disease.
