Titanium dioxide nanoparticles (TiO2- NPs) are produced in large quantities for an extensive range of applications. They retain variable physicochemical properties, which influence their bioactivity. The condensation synthesis of 3-acetylindol, thiophene-2-carbaldehyde and malononitrile in the existence of TiO2 nanoparticle yields 2-amino-6-(1H-indol-3-yl)-4-(thiophen-2-yl)-4H-pyran-3-carbonitrile derivatives. The yielded compound 2 reacted with (formic acid, formamide, ethyl chloroacetate, chloroacetyl chloride, thiourea and sodium nitrite). This three-combination system is safe, ecologically friendly, and non-toxic. The proposed system helped in time preservation and reduction in chemical consumption. The synthesized compounds were screened for antiviral activity against Vero cells (HAV). Antiviral impact percent for samples 2, 5, 6 and 7 versus HAV were 81.98, 91.05, 9.21, and 21.95%, respectively. The viral efficacy of Sample 5 was the strongest against HAV.