Green approach to the synthesis of α-aminophosphonate-tetrahydroisoquinoline hybrids and their anti-cholinesterase activity

MARCHÁN-GARCÍA, JOAQUÍN; BUXADERAS, EDUARDO; STRATICO, DANTE NICOLÁS; RICHMOND, VICTORIA; CAVALLARO, VALERIA; MURRAY, ANA PAULA; RADIVOY, GABRIEL; MOGLIE, YANINA

BIOORGANIC CHEMISTRY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2024 vol. 143

0045-2068

A series of 19 novel α-aminophosphonate-tetrahydroisoquinoline hybrids were synthesized through a cross dehydrogenative coupling reaction between N-aryl-tetrahydroisoquinolines and dialkylphosphites, using tertbutyl hydroperoxide as oxidazing agent. This simple procedure provided products with high atom economy and moderate to high yields. In vitro cholinesterase inhibitory activity of these compounds was evaluated. All the synthesized compounds showed good to excellent selective inhibition against butyrylcholinesterase. Compound 3bc was found to be the most active derivative with an IC50 of 9 nM. Molecular modelling studies suggested thatthe inhibitor is located in the peripheral anionic site (PAS) of the enzyme and interacts with some residue of the catalytic anionic site. Kinetic studies revealed that 3bc acts as a non-competitive inhibitor. Predicted ADME showed good pharmacokinetics and drug-likeness properties for most hybrids. Each newly synthesized compound was characterized by IR, 1H NMR, 13C NMR, 31P NMR spectral studies and also HRMS. The results of this study suggest that α-aminophosphonate-tetrahydroisoquinoline hybrids can be promising lead compounds in the discovery of new and improved drugs for the treatment of Alzheimer’s disease and related neurodegenerativedisorders.