One-Pot Synthesis of 4,6-Diaryl-2-oxo(imino)-1,2-dihydropyridine-3-carbonitrile; a New Scaffold for p38α MAP Kinase Inhibition

Abstract

Two series of new compounds with the general formula 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and their isosteric 2-imino derivatives were synthesized by the multicomponent reaction of the appropriate acetophenone, aromatic aldehyde, ammonium acetate, and malononitrile or ethyl cyanoacetate. The products were obtained with excellent yields. The prepared compounds were evaluated for their in vitro ability to inhibit p38 alpha-MAP kinase. Several compounds showed p38 MAP kinase inhibitory properties with IC(50) as low as 0.07 microM. This is the first time to report compounds with such scaffold as p38 alpha-MAP kinase inhibitors. This asserts the potentiality of multicomponent reactions in drug discovery.

Pyridine‐derived VEGFR‐2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking

“…The chemical entities bearing a 3‐cyano‐4‐aryl‐pyridin‐2‐one moiety or its 2‐amino bioisostere have received considerable attention owing to their ability to elicit cytotoxic antiproliferative activities employing various mechanisms of actions specially kinase inhibition mechanism. [ 22,24–26 ]…”

One‐Pot Synthesis of 3‐Cyano‐2‐pyridones

“…Other examples in preclinical development include A‐769662 (AMPK activator for metabolic disorders) and JNJ‐40068782 (metabotropic glutamate receptor mGluR2 modulator for psychiatric disorders) . In addition to the continuous interest of being explored as cardiotonic agents , 3‐cyano‐2‐pyridones were also explored as antitumor , anticoagulant , anti‐inflammatory, and analgesic agents .…”

“…The majority of the recent syntheses of 3-cyano-2pyridones [5][6][7][8][9][10][11][12][13][14][15][16][17][18] utilized a one-pot four-component condensation (ethyl cyanoacetate, aromatic aldehydes, aromatic ketones, and excess of ammonium acetate) in refluxing ethanol or 2-butanol [41,42]. As a significant improvement from the multiple step reactions, this method offers easy operation and quick assembly from readily available aldehydes and ketones.…”

Synthesis and anticancer properties of novel hydrazone derivatives incorporating pyridine and isatin moieties

“…[36] However, 3-cyano-2-pyridones show remarkable biological and pharmacological properties, particularly antidepressant, [37] anticancer, [38,39] antimicrobial activity, [40] and p38 MAP kinase inhibitory capabilities. [41] Although the developments in chemotherapy increase the fight against cancer, numerous side effects of the drugs used pose serious problems in cancer treatment. A great number of drugs have been used to treat cancer, such as cis-platinum and ruthenium compounds, but good treatable values have not been achieved with existing drugs.…”