Synthesis and CYP24A1 inhibitory activity of (E)-2-(2-substituted benzylidene)- and 2-(2-substituted benzyl)-6-methoxy-tetralones

European Journal of Medicinal Chemistry
Ahmed S AboraiaClaire Simons

Abstract

A series of (E)-2-(2-substituted benzylidene)- and 2-(2-substituted benzyl)-6-methoxy-tetralones were prepared, using an efficient synthetic scheme, and evaluated for their inhibitory activity against cytochrome P450C24A1 (CYP24A1) hydroxylase. In general the reduced benzyl tetralones were more active than the parent benzylidene tetralones. The 2-ethyl and 2-trifluoromethyl benzyl tetralone derivatives (4c and 4b) showed optimal activity in this series with IC(50) values of 1.92 microM and 2.08 microM, respectively compared with the standard ketoconazole IC(50) 0.52 microM. The 2-bromobenzyl tetralone (4d) showed a preference for CYP27A1 (IC(50) 59 nM) over CYP24A1 (IC50 16.3 microM) and may be a useful lead in CYP27A1 inhibition studies. The 2-ethylphenyl benzyl derivative (9c), which showed weak activity against the wild type CYP24A1 (IC(50) 25.57 microM), exhibited enhanced inhibitory activity towards L148F and M416T mutants, this difference in activity for the L148F mutant has been explained using molecular modelling.

Citations

Dec 21, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Guoan ChenNithya Ramnath
May 16, 2013·World Journal of Gastroenterology : WJG·János P KósaPéter Lakatos
Jul 23, 2019·Cell Biochemistry and Function·Carl Jenkinson
Aug 3, 2018·BMJ Open·Abdullah Al-TaiarAnwar Al-Harbi

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