SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: Synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues

In this study, we attempted to derive a comprehensive SAR picture for the c lass of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug c urrently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine de rivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch app roach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional ( 3D) properties of the inhibitors were taken into consideration by performin g a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2, 3,4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previo usly developed in our laboratory. The alignment of the molecules to be subm itted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1 ,2,3,4-tetrahydroacridine and 11H-indeno[ 1,2-b]quinolin-10-ylamine with th e target enzyme. A highly significant CoMFA model was obtained using the st eric field alone, and the features of such a 3D QSAR model were compared wi th the classical QSAR equations previously calculated. The two models appea red consistent, the main aspects they had in common being (a) the individua tion of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically ev aluated, to test the predictive ability of the QSAR models. The 6-bromo-9-a mino-1,2,3,4-tetrahydroacridine was predicted to have a PIC50 value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experim ental IC50 value was equal to 0.066 (+/-0.009) mu M, corresponding to a PIC 50 of 7.18, showing a reasonable agreement between predicted and observed A CI IE inhibition data.