Synthesis, biological screening, and molecular docking of quinazolinone and quinazolinethione as phosphodiesterase 7 inhibitors

• Published in: Archiv der Pharmazie (Weinheim) 2020-01, Vol.353 (1), p.e1900211-n/a
• Main Authors: Elfeky, Sherin M., Sobahi, Tariq R., Gineinah, Magdy M., Ahmed, Nesreen S.
• Format: Article
• Language: English
• Subjects: Binding sites; enzyme inhibition assay; Enzymes; molecular docking; phosphodiesterase 7 inhibitors; phosphodiesterases; quinazolinones; quinazolinonethiones
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201900211

N‐Substituted isatoic anhydrides were used as starting materials for the synthesis of compounds 5–16 through alkali hydrolysis, Schiff base reactions, and oxidation. Compounds 18–23 were obtained by thionation of their oxo isosteres using Lawesson's reagent. Cyclocondesation of anthranilic acid with thiourea afforded compounds 25–27, which were S‐alkylated to afford compounds 28–30, which were thionated using Lawesson's reagent to afford 31–33. The compounds were tested for their in vitro inhibitory activity against the phosphodiesterase 7A (PDE7A) enzyme compared with the selective PDE7 inhibitor BRL50481. All the compounds showed the inhibitory activity on the enzyme at micromolar levels. Compounds 9 and 25 showed the highest inhibitory activity on the enzyme: IC50 = 0.096 and 0.074 μM, respectively, comparable to BRL50481 (IC50 = 0.072 μM). The binding mode and binding affinity of the target compounds at the enzyme PDE7A‐binding site were studied through molecular docking. Compounds 9 and 25 showed good recognition at the enzyme‐binding site and were capable of binding in an inhibitory mode similar to the reference compound BRL50481, forming the necessary interactions with the key amino acids. Docking studies and enzyme assay were in agreement. A new series of 1,2‐disubstituted quinazolin‐4(1H)‐ones, substituted 3‐arylquinazoline‐2,4(1H,3H)‐dithiones, substituted 2‐thioxo‐2,3‐dihydroquinazolin‐4(1H)‐ones, 2‐(benzylthio)‐disubstituted quinazoline‐4(3H)‐ones, and 2‐(benzylthio)‐disubstituted quinazoline‐4(3H)‐thiones were synthesized as novel inhibitors of the cAMP‐specific phosphodiesterase 7A. The new compounds 9 and 25 showed effective inhibitory activity with IC50 values of 0.096 and 0.074 μM, respectively