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dc.contributor.authorSilva, Daniel
dc.contributor.authorMendes, Eduarda
dc.contributor.authorSummers, Eleanor J.
dc.contributor.authorNeca, Ana
dc.contributor.authorJacinto, Ana C.
dc.contributor.authorReis, Telma
dc.contributor.authorAgostinho, Paula
dc.contributor.authorBolea, Irene
dc.contributor.authorJimeno, M. Luisa
dc.contributor.authorMateus, M. Luisa
dc.contributor.authorOliveira-Campos, Ana M. F.
dc.contributor.authorUnzeta, Mercedes
dc.contributor.authorMarco-Contelles, José
dc.contributor.authorMajekova, Magdalena
dc.contributor.authorRamsay, Rona R.
dc.contributor.authorCarreiras, M. Carmo
dc.date.accessioned2020-08-29T23:34:42Z
dc.date.available2020-08-29T23:34:42Z
dc.date.issued2019-08-30
dc.identifier.citationSilva , 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.21594en
dc.identifier.issn1098-2299
dc.identifier.otherPURE: 260556740
dc.identifier.otherPURE UUID: a2bf3daa-a7f7-4a16-9729-e4ef09695e3a
dc.identifier.otherORCID: /0000-0003-1535-4904/work/61369941
dc.identifier.otherScopus: 85071395167
dc.identifier.otherWOS: 000484141800001
dc.identifier.urihttps://hdl.handle.net/10023/20525
dc.descriptionFunding: 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).en
dc.description.abstractBased 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.
dc.language.isoeng
dc.relation.ispartofDrug Development Researchen
dc.rightsCopyright © 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.21594en
dc.subjectNitrile-containing compoundsen
dc.subjectAlzheimer's diseaseen
dc.subjectMAO inhibitorsen
dc.subjectCholinesterase inhibitorsen
dc.subjectAβ1-42 disaggregating agentsen
dc.subjectIn silico studyen
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectNDASen
dc.subject.lccRMen
dc.titleSynthesis, biological evaluation, and molecular modeling of nitrile-containing compounds : exploring multiple activities as anti-Alzheimer agentsen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.identifier.doihttps://doi.org/10.1002/ddr.21594
dc.description.statusPeer revieweden
dc.date.embargoedUntil2020-08-30


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