ABSTRACT
As a privileged class of heterocyclic compounds N-heteroarenes have found enormous applications in many areas including medicinal/pharmaceutical chemistry and drug discovery. Consequently, a wide variety of methods have been reported for their synthesis. While not free from their own limitations the AlCl3 mediated methods appeared to have some particular advantages in preparing a number of useful N-heteroarenes. Besides the famous Friedel-Crafts (FC) alkylation/acylation reactions one such example is AlCl3-induced heteroarylation of arenes and heteroarenes (FC arylation type reactions) that can be used to prepare a certain class of N-heteroarenes in an operationally simple, efficient and cost effective manner. Interestingly, pyridine is not a good substrate in FC alkylation/acylation reactions whereas 2-chloropyridines are indeed effective in heteroarylation reaction. However, no systematic and detailed study regarding the application potential of this method was performed until 2002. Some other examples that emerged in the recent past include AlCl3 induced heteroarylation-cyclization, hydroarylation-heteroarylation, sulfonyl group migration etc. All these innovative methodologies allowed the direct access to several unique and novel N-heteroarenes some of which showed interesting pharmacological properties including anti-inflammatory, anti-cancer and antibacterial activities when tested in vitro. While unlike FC reactions many of these AlCl3 mediated methodologies are still in their initial stage of developments, a continuing effort to uncover their further potential in organic synthesis/medicinal chemistry is necessary. The current article provides an overview of these unique methodologies that highlight the use of AlCl3 beyond FC reactions leading to new N-heteroarenes.
ABSTRACT
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.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/pharmacology , Sulfonamides/chemistry , Triazoles/chemistry , Triazoles/pharmacology , Alkynes/chemistry , Apoptosis/drug effects , Azides/chemistry , Binding Sites , Catalytic Domain , Cell Line, Tumor , Copper/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cycloaddition Reaction , Enzyme Activation/drug effects , Humans , Molecular Docking Simulation , Phosphodiesterase 4 Inhibitors/chemistry , Triazoles/chemical synthesisABSTRACT
A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized are presented.
