ABSTRACT
A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 â¼6-10µM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10µM) that was supported by the docking studies (PLP score 87-94) in silico.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Phosphodiesterase 4 Inhibitors/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HEK293 Cells , Humans , Molecular Docking Simulation , Molecular Structure , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
A new class of 1,2,3-triazol derivatives derived from nimesulide was designed as potential inhibitors of PDE4B. Synthesis of these compounds was carried out via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required azide was prepared via the reaction of aryl amine (obtained from nimesulide) with α-chloroacetyl chloride followed by displacing the α-chloro group by an azide. Some of the synthesized compounds showed encouraging PDE4B inhibitory properties in vitro that is >50% inhibition at 30 µM that were supported by the docking studies of these compounds at the active site of PDE4B enzyme (dock scores ~ -28.6 for a representative compound). Two of these PDE4 inhibitors showed promising cytotoxic properties against HCT-15 human colon cancer cells in vitro with IC50 ~ 21-22 µg/mL.
