Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal 576 104, Karnataka, India.
Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
Bioorg Chem. 2022 Apr;121:105667. doi: 10.1016/j.bioorg.2022.105667. Epub 2022 Feb 9.
In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the CHNHSOR-m moiety at C-3 position of the isocoumarin ring was favorable when the R was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.
在寻找有效且新型的抗炎药物时，我们探索了一类新型的异香豆素衍生物，它们在 C-4 位具有 3-氧代烷基部分。这些化合物是通过 FeCl 催化的异香豆素环构建合成的。该方法涉及 2-炔基苯甲酰胺与烷基乙烯酮的偶联，通过区域选择性环化进行，由于 CO 和 CC 键的形成，得到所需的化合物。大量的异香豆素被合成并在体外针对 PDE4B 进行评估。虽然含有连接在 C-3 芳基环上的氨基磺酰基部分的异香豆素显示出对 PDE4B 的令人鼓舞的抑制作用，但一些没有氨基磺酰基部分的衍生物也显示出相当大的抑制作用。根据 SAR 分析，当 R 选择为芳基或 2-噻吩基时，异香豆素环的 C-3 位置上的 CHNHSOR-m 部分是有利的，而在异香豆素环的 C-7 上存在 F 或 OMe 取代基是有利的。化合物 5f 的 IC 值分别为 0.125±0.032 和 0.43±0.013µM，对 PDE4B 和 4D 具有抑制作用，被确定为初始命中。它与 PDE4B 的 CR3 区域中的 PHE678 残基表现出相互作用，与 PDE4D 的相互作用相对较少。除了在体外显示对其他 PDE 的 PDE4 选择性和 TNF-α抑制作用外，化合物 5f 在腹腔内剂量为 30mg/kg 时，还显示出对关节炎发展的保护作用，并在佐剂诱导的关节炎（AIA）大鼠中具有有效的免疫调节活性。此外，在不同浓度的斑马鱼中进行的系统毒性（例如致畸性、肝毒性和心脏毒性）研究中，未观察到该化合物的显著不良反应。总的来说，作为一种新型、有效、中度选择性和安全的 PDE4B 抑制剂，异香豆素 5f 可以进一步进行药理学研究。
