Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds: Exploring multiple activities as anti-Alzheimer agents.
Drug Dev Res
; 81(2): 215-231, 2020 04.
Article
en En
| MEDLINE
| ID: mdl-31471933
ABSTRACT
Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aß anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 µM), MAO B (0.26 µM), and AChE (52 µM), while 32 exhibited a lead for selective MAO A (0.12 µM) inhibition coupled to AChE (48 µM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aß1-42 , was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aß1-42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 µM), making it a potential lead for Alzheimer's disease application.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Enfermedad de Alzheimer
/
Nitrilos
Límite:
Humans
Idioma:
En
Revista:
Drug Dev Res
Año:
2020
Tipo del documento:
Article
País de afiliación:
Portugal