Abstract：
Quinone-containing compounds have risen as promising anti-inflammatory targets; however, very little research has been directed to investigate their potentials. Accordingly, the current study aimed to design and synthesize group of quinones bearing different substituents to investigate the effect of these functionalities on the anti-inflammatory activities of this important scaffold. The choice of these substituents was carefully done, varying from a directly attached heterocyclic ring to different aromatic moieties linked through a nitrogen spacer. Both in vitro and in vivo anti-inflammatory activities of the synthesized compounds were assessed relative to the positive standards: celecoxib and indomethacin. The in vitro enzymatic and transcription inhibitory actions of all the synthesized compounds were tested against cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1), and 5-lipoxygenase (LOX) and the in vivo gene expression of Interleukin-1, interleukin 10, and Tumor Necrosis Factor-α (TNF-α) were determined. The IC50 against COX-1 and COX-2 enzymes obtained by the immunoassay test revealed promising activities of sixteen compounds with selectivity indices higher than 100-fold COX-2 selectivity. Out of those, four compounds revealed selectivity indices comparable to celecoxib as a reference drug. Furthermore, all the tested compounds inhibited LOX with an IC50 in the range of 1.59-3.11 µM superior to that of the reference drug used; zileuton (IC50 = 3.50 µM). Consequently, these results highlight the promising LOX inhibitory activity of the tested compounds. The obtained in vivo paw edema results showed high inhibitory percentage for the compounds 9a, 9b, and 11a with the significant lower TNF-α relative mRNA expression for compounds 5a, 5d, 9a, 9b, 12d, and 12e. Finally, in silico docking of the most active compounds (5b, 5d, 9a, 9b) against COX2 enzymes presented an acceptable justification of the obtained in vitro inhibitory activities. As a conclusion, Compounds 5b, 5d, 9a, 9b, and 11b showed promising results and thus deserves further investigation.
摘要：
含醌的化合物已成为有希望的抗炎靶标；然而，很少有研究指向调查他们的潜力。因此，本研究旨在设计和合成一组带有不同取代基的醌，以研究这些官能团对这种重要支架的抗炎活性的影响。这些取代基的选择是谨慎的，从直接连接的杂环到通过氮间隔基连接的不同芳族部分。相对于阳性标准:塞来昔布和吲哚美辛评估合成化合物的体外和体内抗炎活性。测试了所有合成化合物对环氧合酶-2（COX-2）的体外酶促和转录抑制作用，环氧合酶-1(COX-1),测定了5-脂氧合酶（LOX）和体内白细胞介素-1，白细胞介素10和肿瘤坏死因子-α（TNF-α）的基因表达。通过免疫测定测试获得的针对COX-1和COX-2酶的IC50揭示了16种化合物的有希望的活性，其选择性指数高于COX-2选择性的100倍。其中，四种化合物显示的选择性指数与塞来昔布作为参考药物相当。此外，所有受试化合物抑制LOX的IC50范围为1.59-3.11µM，优于使用的参考药物齐留通（IC50=3.50µM）。因此,这些结果突出了测试化合物的有希望的LOX抑制活性。获得的体内爪水肿结果显示化合物9a的高抑制率，9b,和11a，化合物5a的TNF-α相对mRNA表达显着降低，5d,9a,9b,12d,12e最后,最活跃的化合物的硅对接(5b，5d,9a,9b）针对COX2酶的表达了所获得的体外抑制活性的可接受的理由。作为结论,化合物5b,5d,9a,9b,和11b显示出有希望的结果，因此值得进一步研究。
