Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase

•Multiple synthetic routes designed for construction of THPs and related piperidines.•2,6-Differently substituted THPs have been achieved via modified one pot MCR.•Cytotoxicity and Enzyme inhibition against M1 family of aminopeptidases.•THPs selectively inhibit hPSA among M1 family of aminopeptidases.•Four compounds exhibited hPSA enzyme inhibition equal to or better than puromycin.

Efficient one-pot five-component synthetic protocols for highly functionalized tetrahydropyridines (THPs) and their biological evaluation have been illustrated. Synthesis of novel functionalized tetrahydropyridines containing differential substitutions at 2,6-positions has been achieved via a modified MCR. Cytotoxic studies of 23 synthesized compounds have been carried out against three different cell lines, namely A-549, HeLa and HepG2, wherein some compounds have displayed appreciable cytotoxicity. Further, investigation of enzyme inhibition by the synthesized THPs has been carried out against four members of M1 family aminopeptidases. Several compounds have selectively inhibited only one member of this enzyme family i.e., human puromycin sensitive aminopeptidase (hPSA). Among the compounds; 4b, 9b, 9e and 10a demonstrated best inhibition against hPSA.

Graphical abstractSynthesis, cytotoxicity and enzymatic studies of piperidine analogues have been disclosed here. An investigation reveals that functionalized THPs and their derivatives have been found to be selective inhibitors of hPSA enzyme among M1 class of aminopeptidases.Figure optionsDownload full-size imageDownload as PowerPoint slide