Synthesis and biological evaluation of novel pyridine derivatives as potential anticancer agents and phosphodiesterase-3 inhibitors

• We synthesized pyridine derivatives as phosphodiesterase inhibitors.
• Increasing cAMP concentration may induce apoptosis signals.
• We examined phosphodiesterase inhibition in vitro and in silico.
• We examined cytotoxicity of synthesized compounds.
• We found correlation between phosphodiesterase inhibition and cytotoxicity.

Phosphodiesterases (PDEs) have been studied in a variety of tumours; data have suggested that the levels of PDE activities are elevated and, therefore, the ratios of cGMP to cAMP are affected. In addition, PDE inhibitors are potential targets for tumour cell growth inhibition and induction of apoptosis. Nonselective PDE inhibitors, such as theophylline or aminophylline, are known regulators of growth in a variety of carcinoma cell lines, suggesting a potential role for PDE inhibitors as anticancer drugs.In the current study, we reported the synthesis of novel derivatives of 6-aryl-4-imidazolyl-2-imino-1,2-dihydropyridine-3-carbonitriles (Ia,b,c) and their 2-oxo isosteres (IIa,b,c,d). All the compounds were evaluated for their PDE3A inhibitory effects, as well as their cytotoxic effects on MCF-7 and HeLa cell lines. Moreover, structure–activity relationships were studied.4-(1-benzyl-2-ethylthio-5-imidazolyl)-6-(4-bromophenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ib) exhibited the strongest PDE3A inhibitory effects with an IC50 of 3.76 ± 1.03 nM. Compound Ib also showed the strongest cytotoxic effects on both the HeLa and MCF-7 cells with an IC50 of 34.3 ± 2.6 μM and 50.18 ± 1.11 μM, respectively. There was a direct correlation between PDE3 inhibition and anticancer activity for the synthesised compounds.The data reported here support our view that PDEs represent promising cellular targets for antitumor treatment.

The possible cytotoxic activity of synthesized novel pyridine derivatives was possibly due to inhibition of phosphodiesterase resulting in increasing cAMP intracellular and thus inducing apoptosis signals.Figure optionsDownload as PowerPoint slide