SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors:  Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues

Abstract

In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently 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 derivatives 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 approach, 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 performing 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 previously developed in our laboratory. The alignment of the molecules to be submitted 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 the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation 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 evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.

Modulation of Binding Strength in Several Classes of Active Site Inhibitors of Acetylcholinesterase Studied by Comparative Binding Energy Analysis

“…On the other hand, for huprines, the inhibitory activity was determined using enzyme from either bovine or human (x3, x5, and x7) erythrocytes. Moreover, the experiments were performed by using either radiometric 33 (for some tacrine derivatives 24 and the dihydroquinazolines 28 ) or spectrophotometric 34 (for some tacrine derivatives, 25 the huprines, 26,27 and the test set 29 ) techniques. Nevertheless, the consistency of the data was supported by inspection of the inhibitory activity for tacrine, which was used as the reference compound in all of these studies.…”

Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

“…Among them, some substituted analogues of tacrine, a reversible inhibitor of AChE that was launched in 1993 as the first drug for the symptomatic treatment of AD (35), seem to be promising, sufficiently effective reversible inhibitors of AChE, suitable for the pharmacological pretreatment of nerve agent poisonings. Especially, tacrine derivatives substituted in the position 6 of the tetrahydroacridine moiety (such as 6-chlorotacrine) were found to be very promising reversible inhibitors od AChE because they exerted relative steric freedom and favorable electron-attracting effect that represents a possibility of a hydrophobic interaction between some amino acid residues and substituents in position 6 of tacrine in the active site of AChE (36). The IC 50 value of 6-chlorotacrine was calculated for human AChE and corresponds to 0.2 ± 0.001 µM.…”

Molecular Docking studies and in-silico ADMET Screening of Some novel Oxazine substituted 9-Anilinoacridines as Topoisomerase II Inhibitors

“…The intercalative property was referred to the planar aromatic system of the acridine moiety. In the same context, acridines have gained strong ground for various biological activities like antimicrobial, 1 antioxidant, 2 anticancer, [3][4][5] antimalarial, 6 analgesic, 7 antileishmanial, 8 antinociceptive, 9 acetyl cholinesterase inhibitors 10 and antiherpes 11 etc. Amsacrine is the best known compound of 9-anilinoacridines series.…”