Dengue virus infection has been posing alarming economic and social burden on affected nations. It is estimated that 50-100 million dengue infections occur annually with over 2.5 billion people at risk for endemic transmission. In the effort to develop effective antiviral agents, we previously reported potential antiviral activities from selected array of natural products and compounds against dengue virus serotype 2 (DV2). In this study, we report the synthesis of two efficacious novel compounds, YK51 and YK73, and their activities against DV2 replication. Both compounds were chemically synthesised from nicotinic acid using a modified method for the synthesis of dihydropyridine. The products were tested with cell-based assays against DV2 followed by a serine protease assay. As a result, both YK51 and YK73 exhibited intriguing antiviral properties with EC50 of 3.2 and 2.4 µM, respectively. In addition, YK51 and YK73 were found to attenuate the synthesis of intracellular viral RNA and protect the switching of non-classic mechanism of protein translation. These compounds demonstrated inhibitory properties toward the activity of DV2 serine protease in a dose dependent manner. These findings demonstrate that both YK51 and YK73 serve as DV2 serine protease inhibitors that abrogate viral RNA synthesis and translation. Further investigation on these compounds to corroborate its therapeutic properties towards dengue is warranted.