Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

Abstract

Phosphodiesterase 4 (PDE4) is a key enzyme involved in the hydrolysis of cyclic adenosine monophosphate (cAMP) and widely expressed in several types of cancers. The inhibition of PDE4 results in an increased concentration of intracellular cAMP levels that imparts the anti‐inflammatory response in the target cells. In the present report, two series of triazolo‐pyridine dicarbonitriles and substituted dihydropyridine dicarbonitriles were synthesized using green protocol (TBAB in refluxed water). We next evaluated the title compounds for their cytotoxicity towards lung cancer (A549) cells and identified 7′‐[4‐(methylsulfonyl)phenyl]‐5′‐oxo‐1′,5′‐dihydrospiro[cyclohexane‐1,2′‐[1,2,4]triazolo[1,5‐a]pyridine]‐6′,8′‐dicarbonitrile (5h) and 7′‐(1‐methyl‐1H‐imidazol‐2‐yl)‐5′‐oxo‐1′,5′‐dihydrospiro[cyclohexane‐1,2′‐[1,2,4]triazolo[1,5‐a]pyridine]‐6′,8′‐dicarbonitrile (5j) as lead analogs with the IC50 values of 15.2 and 24.1 μm, respectively. Furthermore, all the new compounds were tested for PDE4 inhibitory activity and 5j showed relatively good inhibitory activity towards PDE4 with inhibition of 50.9 % at 10 μm. In silico analysis demonstrated the favorable interaction of the title compounds with the target enzyme. Taken together, the present study introduces a new scaffold for the development of novel PDE4 inhibitors to fight against inflammatory diseases.

Methylene Components Exchange in the Reaction of Cyanoacetohydrazide with 2-Amino-4-arylbuta-1,3-diene-1,1,3-tricarbonitriles

“…Such compounds are of interest as starting materials for the preparation of polyazaheterocycles with a bridging nitrogen atom, namely fused 1,2,4-triazines 5 [7,8], 1,2,4,3-triazaphospholo [1,5-a]pyridines 6 [9], [1,2,4]triazolo [1,5-a]pyridines 7 [10][11][12], pyrido [1,2-b] [1,2,4]triazepines 8 [13][14][15][16], and nicotinonitrile derivatives 9 [3] (Scheme 1). Compounds 4 are also promising lowmolecular-weight ligands with an antitumor effect for binding VEGFR-2 kinase [17], phosphodiesterase PDE4 [18], new antibacterial and fungicidal drugs [19], etc. In addition, 1,6-diaminopyridines 4 are used to obtain materials for nonlinear optics [8], azaheterocycles with anticancer action [11,[20][21][22], as well as PGE 2 inhibitors with anti-inflammatory activity [23].…”

Novel 1,3,4-oxadiazole Targets STAT3 Signaling to Induce Antitumor Effect in Lung Cancer

“…4.2.9. In silico Studies Discovery Studio 2.5 version of Insight II from the Accelrys program was used for molecular docking analysis as described earlier [69]. The structure-based analyses were subjected to STAT3β homodimer (PDB ID: 1BG1) [70].…”

Triazole Appended Phosphines: Synthesis, Palladium Complexes, and Catalytic Studies

“…Triazole, though a strong ligand, is anticipated to acquire intriguing ambient properties by incorporating other triazole‐skeleton moieties such as triazole‐pyridine, triazole‐furan and triazole‐heterocyclic compounds . In recent years there is an upsurge interest to synthesize a wide range of triazole based phosphine ligands by incorporating phosphorus moieties on ring atoms or onto the exocyclic groups because of their importance in coordination chemistry and homogeneous catalysis.…”