A search for antiinflammatory therapies: Synthesis, in silico investigation of the mode of action, and in vitro analyses of new quinazolin‐2,4‐dione derivatives targeting phosphodiesterase‐4 enzyme
Aboubakr H. Abdelmonsef, Mohamed Abdel-Hakeem, Ahmed Mohamed Mosallam, Hussain Temairk, Mohamed El‐Naggar, Hend Okasha, Huda R. M. Rashdan
Abstract
Abstract Inflammation is the response of the body's immune system to harmful stimuli. The expression of phosphodiesterase 4 enzyme (PDE4) was demonstrated in many inflammatory cells. Thus, it was considered an attractive therapeutic target for combating inflammatory disorders. In the present study, a novel class of quinazolin‐2,4‐dione analogues 1‐17a,b was synthesized. Structures of the newly synthesized compounds were characterized by means of spectral and elemental analysis. Additionally, molecular docking studies for the new synthetic compounds were performed using PyRx—virtual screening tool to demonstrate the possible binding pattern mode of interactions within the active site region of the PDE4 enzyme. The antiinflammatory activity of the synthesized compounds was also in vitro examined using inhibition of protein denaturation, anti‐proteinase effect, and membrane stabilization assay. The in silico docking studies revealed that the newly synthesized compounds were well accommodated by the active site region of the target protein through a network of noncovalent interactions such as hydrogen bonds and pi‐stacking, which contributed to the enhancement of affinity and stability between the compounds and the target protein. They exhibited better docking scores when compared with reference drugs diclofenac and coumarin. In addition, in vitro testing revealed that the compounds had moderate to good antiinflammatory effects. The biological study agreed with in silico approach, which revealed that the compounds had promising antiinflammatory activity. Hence, our detailed results can facilitate the rational drug design targeting PDE4 enzyme.