Bošković Jelena, Dobričić Vladimir, Mihajlović Marija, Kotur-Stevuljević Jelena, Čudina Olivera
Department of Pharmaceutical Chemistry, University of Belgrade-Faculty of Pharmacy, 11221 Belgrade, Serbia.
Department of Medical Biochemistry, University of Belgrade-Faculty of Pharmacy, 11221 Belgrade, Serbia.
Pharmaceuticals (Basel). 2023 Apr 6;16(4):549. doi: 10.3390/ph16040549.
Various dual inhibitors of COX-2 and 5-LOX enzymes have been developed so far in order to obtain more effective and safer anti-inflammatory drugs. The aim of this study was to design and synthesize new dual COX-2 and 5-LOX inhibitors, and to evaluate their enzyme inhibition potential and redox properties. Thirteen compounds (-) were designed taking into account structural requirements for dual COX-2 and 5-LOX inhibition and antioxidant activity, synthesized, and structurally characterized. These compounds can be classified as -hydroxyurea derivatives (, and ), 3,5-di-tert-butylphenol derivatives (, , , and ), urea derivatives (, and ) and "type B hydroxamic acids" ( and ). COX-1, COX-2 and 5-LOX inhibitory activities were evaluated using fluorometric inhibitor screening kits. The evaluation of the redox activity of newly synthesized compounds was performed in vitro in the human serum pool using redox status tests. The prooxidative score, the antioxidative score and the oxy-score were calculated. Seven out of thirteen synthesized compounds (, , , , , and ) proved to be dual COX-2 and 5-LOX inhibitors. These compounds expressed good COX-2/COX-1 selectivity. Moreover, dual inhibitors , , , and showed good antioxidant properties.
为了获得更有效、更安全的抗炎药物，目前已开发出多种COX-2和5-LOX酶的双重抑制剂。本研究的目的是设计并合成新型COX-2和5-LOX双重抑制剂，并评估它们的酶抑制潜力和氧化还原特性。考虑到双重抑制COX-2和5-LOX以及抗氧化活性的结构要求，设计了13种化合物（-），进行了合成及结构表征。这些化合物可分为-羟基脲衍生物（、和）、3,5-二叔丁基苯酚衍生物（、、、和）、脲衍生物（、和）以及“B型异羟肟酸”（和）。使用荧光抑制剂筛选试剂盒评估COX-1、COX-2和5-LOX的抑制活性。利用氧化还原状态测试在人血清池中体外评估新合成化合物的氧化还原活性。计算促氧化评分、抗氧化评分和氧评分。13种合成化合物中有7种（、、、、、和）被证明是COX-2和5-LOX双重抑制剂。这些化合物表现出良好的COX-2/COX-1选择性。此外，双重抑制剂、、、和表现出良好的抗氧化性能。
