Elrayess Ranza, Elgawish Mohamed Saleh, Elewa Marwa, Nafie Mohamed S, Elhady Sameh S, Yassen Asmaa S A
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Pharmaceuticals (Basel). 2020 Nov 6;13(11):370. doi: 10.3390/ph13110370.
Targeting of cyclooxygenase-2 (COX-2) has emerged as a powerful tool for therapeutic intervention because the overexpression of this enzyme is synonymous with inflammation, cancer, and neurodegenerative diseases. Herein, a new series of 1,2,4-triazole Schiff bases scaffold with aryl and heteroaryl systems were designed, synthesized, structurally elucidated, and biologically evaluated as a potent COX-2 blocker. The rationale beyond the current study is to increase the molecule bulkiness allowing a selective binding to the unique hydrophobic pocket of COX-2. Among the triazole-thiazole hybrids, the one with the para-methoxy moiety linked to a phenyl ring showed the highest In vitro selectivity by COX-2 inhibition assay (IC of 0.04 μM) and in situ anti-inflammatory activity when evaluated using the protein denaturation assay (IC of 0.88 μM) in comparison with commercially available selective COX-2 inhibitor, Celecoxib (IC of 0.05 μM). Towards the COX-2 selectivity, ligand-based three dimensional quantitative structures activity relationship (3D-QSAR) employing atomic-based and field-based approaches were performed and resulted in the necessity of triazole and thiazole/oxazole scaffolds for COX-2 blocking. Furthermore, the molecular modeling study indicated a high selectivity and promising affinity of our prepared compounds to COX-2, especially the hydrophobic pocket and the mouth of the active site holding hydrogen-bonding, hydrophobic, and electrostatic interactions. In Silico absorption, delivery, metabolism, and excretion (ADME) predictions showed that all the pharmacokinetic and physicochemical features are within the appropriate range for human use.
靶向环氧化酶-2（COX-2）已成为一种强大的治疗干预工具，因为这种酶的过表达与炎症、癌症和神经退行性疾病同义。在此，设计、合成、结构解析并生物学评估了一系列新的带有芳基和杂芳基系统的1,2,4-三唑席夫碱支架作为有效的COX-2阻滞剂。当前研究背后的基本原理是增加分子的体积，使其能够选择性地结合到COX-2独特的疏水口袋中。在三唑-噻唑杂化物中，与苯环相连的对甲氧基部分的化合物在COX-2抑制试验（IC为0.04μM）中显示出最高的体外选择性，并且在使用蛋白质变性试验评估时（IC为0.88μM）具有原位抗炎活性，与市售的选择性COX-2抑制剂塞来昔布（IC为0.05μM）相比。针对COX-2选择性，采用基于原子和基于场的方法进行了基于配体的三维定量构效关系（3D-QSAR）研究，结果表明三唑和噻唑/恶唑支架对于COX-2阻断是必要的。此外，分子模拟研究表明我们制备的化合物对COX-2具有高选择性和有前景的亲和力，特别是对疏水口袋以及保持氢键、疏水和静电相互作用的活性位点入口。计算机辅助吸收、分布、代谢和排泄（ADME）预测表明，所有药代动力学和物理化学特征都在适合人类使用的范围内。
