Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors

Abstract

Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2- oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2- imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC50of 27 μM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2- dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC50 of 3 μM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity.

Novel Polyfunctional Pyridines as Anticancer and Antioxidant Agents. Synthesis, Biological Evaluation and <i>in Silico</i> ADME-T Study

“…28,29) Several in silico molecular docking and in vitro testing studies have emphasized the importance of the pyridinecarbonitrile scaffold as novel PDE3 inhibitors and anticancer agents. [30][31][32][33] Among these, compound I ( Fig. 1) stemmed as the most potent PDE3A inhibitor with significant cytotoxic potential.…”

Green Synthesis of Novel 5-Arylazo-2- [(2S, 3S, 4R, 5R)-3, 4, 5- trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yloxy]-4, 6-dimethyl 3-nicotinonitrile.

“…Also from the amazing character of some pyridine is its high fluorescence activities which was used as molecular sensor of picric acid [3].…”

“…Genetic mutation and acquisition of mobile drug resistance genes of microorganisms is a very great resistance and barrier in treating animal and human patients with infectious diseases [4,5]. The importance of the synthesis of novel derivatives of pyridine nucleosides due to their potential use to treat various diseases, such as hepatitis cancer and microbial infections [6][7][8][9][10].…”

“…Many uses of pyridines derivatives were investigated in the recent decades especially fluorinated derivatives. One of the recent researches discovered that high tuberculostearic activity of pyridine was observed [1,2].Also from the amazing character of some pyridine is its high fluorescence activities which was used as molecular sensor of picric acid [3].It has been of great importance in the exploring of some novel antimicrobial compounds in veterinary as well as human medicine worldwide. Genetic mutation and acquisition of mobile drug resistance genes of microorganisms is a very great resistance and barrier in treating animal and human patients with infectious diseases [4,5].…”

“…Genetic mutation and acquisition of mobile drug resistance genes of microorganisms is a very great resistance and barrier in treating animal and human patients with infectious diseases [4,5]. The importance of the synthesis of novel derivatives of pyridine nucleosides due to their potential use to treat various diseases, such as hepatitis cancer and microbial infections [6][7][8][9][10].Fluorinated derivatives of pyridines are of high significance in pharmaceutical and medicinal chemistry [11]. Synthesis of poly substituted fluroarylazopyridone by using green protocol is of great effect in synthetic chemistry and also in pharmaceutical chemistry [12].…”