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Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds : exploring multiple activities as anti-Alzheimer agents

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Silva2019acceptedDDR.pdf (22.88Mb)
Date
30/08/2019
Author
Silva, Daniel
Mendes, Eduarda
Summers, Eleanor J.
Neca, Ana
Jacinto, Ana C.
Reis, Telma
Agostinho, Paula
Bolea, Irene
Jimeno, M. Luisa
Mateus, M. Luisa
Oliveira-Campos, Ana M. F.
Unzeta, Mercedes
Marco-Contelles, José
Majekova, Magdalena
Ramsay, Rona R.
Carreiras, M. Carmo
Keywords
Nitrile-containing compounds
Alzheimer's disease
MAO inhibitors
Cholinesterase inhibitors
Aβ1-42 disaggregating agents
In silico study
RM Therapeutics. Pharmacology
NDAS
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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 Aβ 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 Aβ1–42, was very weak, the effect of 63 and 65 , and of the new compound 75 , indicated that these compounds were able to disaggregate Aβ1–42 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.
Citation
Silva , D , Mendes , E , Summers , E J , Neca , A , Jacinto , A C , Reis , T , Agostinho , P , Bolea , I , Jimeno , M L , Mateus , M L , Oliveira-Campos , A M F , Unzeta , M , Marco-Contelles , J , Majekova , M , Ramsay , R R & Carreiras , M C 2019 , ' Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds : exploring multiple activities as anti-Alzheimer agents ' , Drug Development Research , vol. Early View , DDR-19-0121.R1 . https://doi.org/10.1002/ddr.21594
Publication
Drug Development Research
Status
Peer reviewed
DOI
https://doi.org/10.1002/ddr.21594
ISSN
1098-2299
Type
Journal article
Rights
Copyright © 2019 Wiley Periodicals, Inc. This work has been made available online in accordance with publisher policies or with permission. Permission for further reuse of this content should be sought from the publisher or the rights holder. This is the author created accepted manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1002/ddr.21594
Description
Funding: EC COST Actions D34 and CM1103 for Short-term Scientific Mission funding (EM, DS, MM); the School of Biology at the University of St. Andrews (EJS, RRR); the Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa (AN, ACJ, TR, MCC); FCT, the Portuguese Foundation for Science and Technology (Project PTDC/SAU-NEU/64151/2006 (MCC), and project grant (DS) Vega 2/0127/18 and the contract No. APVV-15-0455 of Slovak Research and Development Agency (MM).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/20525

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