For the first time the template containing structural features of more than one NSAIDs and the 1,2,3-triazole ring was explored for the identification of potential cytotoxic agents. These new and complex molecules were predicted to be effective inhibitors of PDE4B by molecular modelling studies in silico. The multi-step synthesis of these compounds were carried out starting from the well-known drug nimesulide and involved the use of copper-catalyzed azide-alkyne cycloaddition (CuAAC) approach as the key step. Mainly two types of compounds e.g. 1-aryl-1H-1,2,3-triazoles and N-aryl-2-(1H-1,2,3-triazol-1-yl)acetamide derivatives were synthesized by using this method in good yields. The in vitro screening of these compounds against two cancer cell lines e.g. HCT-15 (human colon cancer cell line) and NCI-H226 (human lung cancer cell line) using a colorimetric MTT assay allowed identification of two preliminary hit molecules i.e. 8a and 8f. The SAR (Structure Activity Relationship) analysis indicated that the presence of an amide linker between the aryl ring and the 1,2,3-triazole moiety was favorable for the activities. The compound 8a and 8f showed significant inhibition of PDE4B in vitro and good interactions with this protein in silico suggesting PDE4B as their potential target. The usefulness and concerns of these molecules in the light of computational ADME prediction were analyzed. Overall, novel molecules were identified as potential cytotoxic agents for further study.