Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells.
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.
Department of Chemistry, MNR Degree & PG College, Kukatpally, Hyderabad 500085, India; Centre for Chemical Sciences and Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500085, India.
Jyoti
J
Mareddy
Suresh Babu
SB
Nallapati
Jayasree
J
Anireddy
Yumnam Priyadarshini
YP
Devi
Lakshmi Narasu
LN
Mangamoori
Ravikumar
R
Kapavarapu
Sarbani
S
Pal
D000480:Alkynes / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D061565:Cycloaddition Reaction; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000480:Alkynes; D001386:Azides; D058988:Phosphodiesterase 4 Inhibitors; D013449:Sulfonamides; D014230:Triazoles; D003300:Copper; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C012655:nimesulide
1,2,3-Triazole; Cycloaddition; Cytotoxic activities; Nimesulide; PDE4B