ホスホジエステラーゼ7阻害剤としてのキナゾリノンおよびキナゾリネチオンの合成、生物学的スクリーニング、および分子ドッキング

N-置換イサート酸化除油は、アルカリ加水分解、シッフ塩基反応、および酸化を介した化合物5-16の合成のための出発材料として使用されました。Compounds 18-23 were obtained by thionation of their oxo isosteres using Lawesson's reagent.アントラニル酸のチオレア酸のサイクロコンデューションは、化合物25-27を提供し、28〜30化化合物28-30を提供するためにS-アルキル化されました。この化合物は、選択的PDE7阻害剤BRL50481と比較して、ホスホジエステラーゼ7a（PDE7A）酵素に対するin vitro阻害活性についてテストされました。All the compounds showed the inhibitory activity on the enzyme at micromolar levels.化合物9および25は、BRL50481（IC50 =0.072μm）に匹敵する、それぞれ酵素であるIC50 = 0.096および0.074μMで最も高い阻害活性を示しました。The binding mode and binding affinity of the target compounds at the enzyme PDE7A-binding site were studied through molecular docking.化合物9および25は、酵素結合部位で良好な認識を示し、参照化合物Brl50481と同様に阻害モードで結合することができ、重要なアミノ酸との必要な相互作用を形成しました。Docking studies and enzyme assay were in agreement.

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.