Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Abstract

Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active.

New Tacrine−Huperzine A Hybrids (Huprines): Highly Potent Tight-Binding Acetylcholinesterase Inhibitors of Interest for the Treatment of Alzheimer's Disease

“…Most of the new compounds (rac-19, rac-24, rac-26, and rac-27) and rac-20 and rac-30, whose syntheses were previously reported, 19,20 are clearly more active than tacrine and (-)-huperzine A as bovine AChE inhibitors. As previously observed in this series of compounds, 17 the levorotatory enantiomers [(-)-20, (-)-26, and (-)-30] are more active than the corresponding racemic mixtures, while the dextrorotatory enantiomers are clearly less potent. With the exception of rac-29, which is the sole compound substituted at position 2, the rest of compounds (rac-25, rac-28, and rac-31) are slightly more potent than (-)-huperzine A.…”

“…Moreover, the introduction of a fluorine substituent at position 3 (rac-18) was also found to be advantageous, leading to a compound 15 times more active than tacrine in inhibiting AChE from bovine erythrocytes. 17 Likewise, the AChE inhibitory activity of the levorotatory enantiomers was roughly twice that of the racemic mixtures, while the dextrorotatory enantiomers were much less active. Molecular modeling of the interaction of these compounds with Torpedo californica AChE (TcAChE) suggested that they behave as true tacrine-huperzine A hybrids, since the 4-aminoquinoline and bicyclo[3.3.1]-nonadiene subunits roughly occupy the same positions of the corresponding moieties in tacrine and (-)-huperzine A, respectively, as determined from their crystallographic complexes with AChE.…”

“…Molecular modeling of the interaction of these compounds with Torpedo californica AChE (TcAChE) suggested that they behave as true tacrine-huperzine A hybrids, since the 4-aminoquinoline and bicyclo[3.3.1]-nonadiene subunits roughly occupy the same positions of the corresponding moieties in tacrine and (-)-huperzine A, respectively, as determined from their crystallographic complexes with AChE. 17,18 Later, replacement of fluorine by chlorine at position 3 (rac-30) was found to improve the inhibitory activity, leading to an inhibition constant (K i ) for human AChE around 30 pM, which means an affinity around 1200-fold higher than that of tacrine. 20 Since these derivatives bind to AChE with very high affinity, it is of interest to explore in more detail the effect of these structural changes on the AChE inhibitory activity.…”

The Molecular Basis for Inhibition of BphD, a C-C Bond Hydrolase Involved in Polychlorinated Biphenyls Degradation

“…It is possible that the compatibility of chlorine versus fluorine with this hydrophobic pocket versus the solution may account for the greater accumulation of 3-Cl HOPDA in the E⅐S e binding mode, although this may also reflect the inability of 3-Cl HOPDA to access the E⅐S red conformation, as discussed below. Similarly, acetylcholine esterase binds huprine X such that a hydrophobic pocket is fully occupied by the inhibitor's chlorine atom, and substitution with fluorine reduces binding affinity (41,42). In the crystal, the binding of 3-Cl HOPDA is also monomorphic, whereas the carboxylate, 2-OH, and 3-F moieties of 3,10-diF HOPDA are not well ordered.…”

Study of the interaction of Huperzia saururus Lycopodium alkaloids with the acetylcholinesterase enzyme

“…[25,26] Other AChEIs of relevance, but obtained by synthesis, are Tacrine (4), [27] donepezil (5) [28,29] and rivastigmine (6), [30] the latter being a semi-synthetic derivative of 1. Last but not least, there is a family of compounds originated by a fusion between the tacrine and huperzine A cores, namely the huprine family (7), [31,32] i.e. huprine X (8), [33,34] which also act as useful AChEIs, but are not yet approved by FDA.…”