59021-51-1Relevant articles and documents
Synthesis, biological evaluation, and molecular modeling of nitrile-containing compounds: Exploring multiple activities as anti-Alzheimer agents
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
, p. 215 - 231 (2019/09/03)
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.
Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1)
Schmitt, Sven Marcel,Stefan, Katja,Wiese, Michael
, p. 3018 - 3033 (2016/05/19)
Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay. New compounds with high potency and selectivity were identified. Piperazine residues at position 4 bearing large phenylalkyl side chains proved to be beneficial for MRP1 inhibition. Its replacement by an amino group led to decreased activity. Aliphatic and aliphatic-aromatic variations at position 5 and 6 revealed compounds with IC50 values in high nanomolar range. All investigated compounds had low affinity toward P-glycoprotein (P-gp, ABCB1). Pyrrolopyrimidines with small substituents showed moderate inhibition against breast cancer resistance protein (BCRP, ABCG2).
Synthesis of new tacrine analogues from 4-amino-1H-pyrrole-3-carbonitrile
Salaheldin, Abdellatif M.,Oliveira-Campos, Ana M. F.,Parpot, Pier,Rodrigues, Ligia M.,Oliveira, M. Manuel,Feixoto, Francisco P.
experimental part, p. 242 - 248 (2010/05/15)
An easy preparation of 4-amino-1H-pyrrole-3-carbonitrile derivatives and their transformation into new substituted pyrrolo[3,2-b]pyridines is described. The one-step transformation was carried out via Friedlaender reaction under microwave irradiation and
