Design, synthesis, and pharmacological characterization of some 2‐substituted‐3‐phenyl‐quinazolin‐4(3H)‐one derivatives as phosphodiesterase inhibitors

Abstract

Some 3‐phenyl‐quinazolin‐4(3H)‐one‐2‐thioethers (3a–e, 5a,b, 7a–e, 9a–d, 10a–d, and 12) along with 2‐aminoquinazoline derivatives 13a–c were prepared and screened for their in vitro phosphodiesterase (PDE) inhibitory activity. Some compounds such as 7d,e, 9a,b,d, 10a,d, and 13b exhibited promising activity as compared with the non‐selective PDE inhibitor IBMX. This inhibitory activity was validated by molecular docking in the active site of PDE7A and PDE4 to investigate their selectivity. Furthermore, the most active compound 10d (IC50 = 1.15 μM) was tested in vivo using behavioral tests. Compound 10d was able to pass the blood–brain barrier and improve scopolamine‐induced cognitive deficits. Therefore, this core can be considered as a promising scaffold for further optimization to obtain new compounds with better PDE7A selective inhibition.

Design, synthesis, molecular docking, and molecular dynamic studies of novel quinazoline derivatives as phosphodiesterase 7 inhibitors

“…Additionally, it has been observed that all these quinazoline derivatives possess significant anti-inflammatory activity ( Figure 1 ). It is worth knowing that PDE7 is a cAMP-specific phosphodiesterase enzyme ( Keravis and Lugnier, 2012 ; Amin, et al, 2021 ). PDE7 consists of two members, one of them is PDE7A, which is widely expressed in skeletal muscle and T-lymphocytes.…”