Design, synthesis and anticholinesterase activity of some new α-aminobisphosphonates

Some new alpha-aminomethylenephosphonic acids 1-11 were synthesised and characterised by H-1, C-13, P-31 NMR, IR spectroscopy and elemental analysis. The potencies of these compounds to inhibit human erythrocyte acetylcholinesterase (hAChE, EC 3.1.1.7) were studied by a modified Ellman's method. In addition, the log P values were computed by Hyperchem software. Here, alendronate was used as a reference inhibitor. Results showed that the IC50 values ranged from 9.11 to 28.72 mM. The half maximal inhibitory concentration (IC50) value decreased with an increasing number of carbon atoms of the amine group in compounds 1-5. Also, in most cases, increasing the number of carbon atoms led to enhancement of the toxicity as predicted by the log P values. Using Lineweaver-Burk and Dixon analysis, it was indicated that compounds 1-10 are mixed inhibitors while compound 11 is a coupling or uncompetitive inhibitor. The results showed that the electronic changes have ignorable effects, steric influence is important in some cases, but the lipophilicity parameter is the most significant factor in hAChE inhibition by bisphosphonates.