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

Abstract

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.

Pd(ii)-catalyzed cascade annulation of N-substituted anilines with CO, NH4OAc and aldehydes to N1-substituted 2,3-dihydroquinazolin-4(1H)-ones

“…As an important class of nitrogen-containing heterocycles, N 1-substituted 2,3-dihydroquinazolin-4(1 H )-ones (DHQs) have wide-ranging pharmacological and biological properties, such as anti-inflammatory, 1 anticancer, 2 and analgesic activities, 1 b and the inhibition of protein kinase C-θ, 3 cholinesterases, 4 and phosphodiesterase 7, 5 etc . Some representative bioactive N 1-substituted DHQs are shown in Fig.…”

Tandem Transformation of Indazolones to Quinazolinones through Pd-Catalyzed Carbene Insertion into an N–N Bond

“…In particular, the synthesis of 2,3-di­(hetero)­aryl-2,3-dihydroquinazolin-4­(1 H )-ones has received special attention . Under this domain, several new catalytic systems, including Lewis/organic acids, transition-metal catalysts, nanoparticles, ionic liquids, and silica-supported reagents have been exemplified for the multicomponent reaction between isatoic anhydride, amine (or ammonium acetate), and aldehydes (Scheme a). , Alternatively, the condensation between 2-amino N -arylbenzamide and aldehyde can be used to furnish 2,3-di­(hetero)­aryl-2,3-dihydroquinazolin-4­(1 H )-ones (Scheme b). ,, On the other hand, a two-step protocol, involving ammonium hydroxide-mediated transformation of N -aryl isatoic anhydride to 2-arylaminobenzamide, followed by its condensation with aldehyde has been employed for the preparation of 1,2-di­(hetero)­aryl-2,3-dihydroquinazolin-4­(1 H )-ones (Scheme c) . Although these reported protocols are associated with their own merits and demerits, the evolution of eye-catching strategies with significant advancement in chemistry for preparing 1,2-di­(hetero)­aryl and 2,3-di­(hetero)­aryl-2,3-dihydroquinazolin-4­(1 H )-ones is still in great demand.…”

Advances in Cyclic Nucleotide Phosphodiesterase-Targeted PET Imaging and Drug Discovery

“…61 In particular, ASB16165 was successfully used to treat TNF-α-mediated skin inflammation in a mouse model of TPA-induced dermatitis. 62 In the past two decades, a series of heterocyclic small molecules, including benzo-thienothiadiazine dioxides, 63 pyrimidines, 64 thiadiazoles, 65 spiroquinazolinones, 66 sulfides, 67 thieno[3,2-d]pyrimidinones, 68 quinazolinones, and quinazolinethiones, 69 were studied as potent and selective PDE7 inhibitors. A summary of selected PDE7 inhibitors is depicted in Figure 5.…”