Laboratory of Organic & Medicinal Chemistry, Department of Chemistry, Malaviya National Institute of Technology, Jawaharlal Nehru Marg, Jaipur, 302017, India.
College of Pharmacy, Gachon University of Medicine and Science, Incheon, South Korea.
ChemMedChem. 2018 Sep 6;13(17):1817-1832. doi: 10.1002/cmdc.201800318. Epub 2018 Aug 8.
To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH , OC H , OC H ) functional groups at C1/C2 of ring A and an acyl (COCH and COPh) or phenylsulfonyl (SO Ph and SO C H -3-CH ) functionality at the N6 position of ring B of the aporphine scaffold were synthesized and evaluated for their arachidonic acid (AA)-induced antiplatelet aggregation inhibitory activity and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging antioxidant activity, with acetylsalicylic acid and ascorbic acid as standard references, respectively. The preliminary structure-activity relationship related to AA-induced platelet aggregation inhibitory activity results showed that the aporphine analogues 1-[1,2,9,10-tetramethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone and 1-[2-(benzyloxy)-1,9,10-trimethoxy-6a,7-dihydro-4H-dibenzo[de,g]quinolin-6(5H)-yl]ethanone to be the best compounds of the series. Moreover, the DPPH free-radical-scavenging antioxidant activity results demonstrated that the aporphine analogues 1,2,9,10-tetramethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2-ethoxy-1,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 1-ethoxy-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, 2,9,10-trimethoxy-6-(methylsulfonyl)-1-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline, and 1-(benzyloxy)-2,9,10-trimethoxy-6-(methylsulfonyl)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline were the best compounds of the series. Moreover, in silico molecular docking simulation studies of the active analogues were also performed.
为了探索阿朴啡生物碱的潜力，我们合成了一系列新型的功能化阿朴啡类似物，这些类似物在阿朴啡骨架的环 A 的 C1/C2 位具有烷氧基（OCH3、OC2H5、OC3H7）官能团，在环 B 的 N6 位具有酰基（COCH3 和 COPh）或苯磺酰基（SO2Ph 和 SO2C2H4-3-CH3）官能团。我们对这些类似物进行了评价，以研究它们对花生四烯酸（AA）诱导的抗血小板聚集活性和 2,2-二苯基-1-苦基肼基（DPPH）自由基清除抗氧化活性，以阿司匹林和抗坏血酸分别作为标准参考。与 AA 诱导的血小板聚集抑制活性相关的初步构效关系研究结果表明，阿朴啡类似物 1-[1,2,9,10-四甲氧基-6a,7-二氢-4H-二苯并[de,g]喹啉-6(5H)-基]乙酮和 1-[2-（苯甲氧基）-1,9,10-三甲氧基-6a,7-二氢-4H-二苯并[de,g]喹啉-6(5H)-基]乙酮是该系列中最好的化合物。此外，DPPH 自由基清除抗氧化活性结果表明，阿朴啡类似物 1,2,9,10-四甲氧基-6-（甲基磺酰基）-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉、2-乙氧基-1,9,10-三甲氧基-6-（甲基磺酰基）-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉、1-乙氧基-2,9,10-三甲氧基-6-（甲基磺酰基）-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉、2,9,10-三甲氧基-6-（甲基磺酰基）-1-丙氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉和 1-（苯甲氧基）-2,9,10-三甲氧基-6-（甲基磺酰基）-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉是该系列中最好的化合物。此外，我们还对活性类似物进行了计算机分子对接模拟研究。
