Design, synthesis and biological evaluation of new 2-aminothiazole scaffolds as phosphodiesterase type 5 regulators and COX-1/COX-2 inhibitors

摘要

A new series of 2-aminothiazole derivatives was designed and prepared as phosphodiesterase type 5 (PDE5) regulators and COX-1/COX-2 inhibitors. The screening of the synthesized compounds for PDE5 activity was carried out using sildenafil as a reference drug. Strikingly, compounds 23a and 23c were found to have a complete inhibitory effect on PDE5 (100%) at 10 μM without causing hypotension and the limited side effect of PDE5 inhibitors, suggest a distinctive therapeutic role of these derivatives in erectile dysfunction. On the other hand, compounds 5a , 17 , 21 and 23b increased the PDE5 activity (PDE5 enhancers) at 10 μM. In addition, the study includes the screening of the COX-1/COX-2 inhibition induced by the synthesized compounds. All tested compounds have an inhibitory effect against COX-1 activity (IC _(50) = 1.00–6.34 μM range) and COX-2 activity (IC _(50) = 0.09–0.71 μM range). Moreover, a molecular docking study was implemented to reveal the binding interactions of potent compounds in the binding sites of PDE5 (PDB ID 2H42), COX-1 and COX-2 (PDB ID 3LN1) enzymes. For the interaction with the PDE5 enzyme, activator compounds had a strong binding mode (HB with Gln817:A) than inhibitory derivatives. Both types of compounds are considered as PDE5 regulators. This novel finding will encourage us to discover a new pharmacological application of small chemical entities as the PDE5 enhancer, or will lower side effects as PDE5 inhibitors. All active compounds adopted the Y-shape along the COX-2 active site.