Dengue　virus　(DENV)　is　a　major　mosquito-borne　human　pathogen　in　tropical　countries;　however,　there　are　currently　no　targeted　antiviral　treatments　for　DENV　infection.　Compounds　27　and　29　have　been　reported　to　be　allosteric　inhibitors　of　DENV　RdRp　with　potent　inhibitory　effects.　In　this　study,　the　structures　of　compounds　27　and　29　were　optimized　using　computer-aided　drug　design　(CADD)　approaches.　Nine　novel　compounds　were　synthesized　based　on　rational　considerations,　including　molecular　docking　scores,　free　energy　of　binding　to　receptor　proteins,　predicted　Absorption,　Distribution,　Metabolism,　Excretion,　and　Toxicity　(ADMET)　parameters,　structural　diversity,　and　feasibility　of　synthesis.　Subsequently,　the　anti-DENV　activity　was　assessed.　In　the　cytopathic　effect　(CPE)　assay　conducted　on　BHK-21　cells　using　the　DENV2　NGC　strain,　both　SW-b　and　SW-d　demonstrated　comparable　or　superior　activity　against　DENV2,　with　IC50　values　of　3.58　+/-　0.29　mu　M　and　23.94　+/-　1.00　mu　M,　respectively,　compared　to　that　of　compound　27　(IC50　=　19.67　+/-　1.12　mu　M).　Importantly,　both　SW-b　and　SW-d　exhibited　low　cytotoxicity,　with　CC50　values　of　24.65　mu　mol　and　133.70　mu　mol,　respectively,　resulting　in　selectivity　indices　of　6.89　and　5.58,　respectively.　Furthermore,　when　compared　to　the　positive　control　compound　3　＇-dATP　(IC50　=　30.09　+/-　8.26　mu　M),　SW-b　and　SW-d　displayed　superior　inhibitory　activity　in　an　enzyme　inhibitory　assay,　with　IC50　values　of　11.54　+/-　1.30　mu　M　and　13.54　+/-　0.32　mu　M,　respectively.　Molecular　dynamics　(MD)　simulations　elucidated　the　mode　of　action　of　SW-b　and　SW-d,　highlighting　their　ability　to　enhance　pi-pi　packing　interactions　between　benzene　rings　and　residue　W795　in　the　S1　fragment,　compared　to　compounds　27　and　29.　Although　the　transacylsulphonamide　fragment　reduced　the　interaction　between　T794　and　NH,　it　augmented　the　interaction　between　R729　and　T794.　In　summary,　our　study　underscores　the　potential　of　SW-b　and　SW-d　as　allosteric　inhibitors　targeting　the　DENV　NS5　RdRp　domain.　However,　further　in　vivo　studies　are　warranted　to　assess　their　pharmacology　and　toxicity　profiles.