Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design, Synthesis, Structure-Activity Relationships, Biological Evaluations, and in silico Molecular Docking Studies.

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.