In recent years, the investigation of acetylcholinesterase (AChE) inhibitors has gained further interest, because the involvement of the peripheral site of the enzyme in the beta-amyloid (Abeta) aggregation process has been disclosed. We present here, for the first time, a direct evidence of the Abeta antiaggregating action of an AChE inhibitor (AP2238) purposely designed to bind at both the catalytic and the peripheral sites of the human enzyme.

Aromatase (P450arom) is a target of pharmacological interest for the treatment of breast cancer. In this paper, we report the design, synthesis, and in vitro biological evaluation of a series of new (di)benzopyranone-based inhibitors of this enzyme. The design of the new compounds was guided by a CoMFA model previously developed for a series of nonsteroidal aromatase inhibitors. Both the chromone and the xanthone nuclei were taken as molecular skeletons, and the functions supposed to be critical for binding to the aromatase active site - a heterocyclic ring (imidazole or 1,3,4-triazole) linked to the aromatic moiety by a methylene unit and an H-bond accepting function (CN, NO(2), Br) located on the aromatic ring at a suitable distance from the heterocyclic nitrogen carrying the lone pair--were attached to them. The chromone, xanthone, and flavone derivatives were prepared by conventional synthetic methods from the appropriate methyl analogues. Aromatase inhibitory activities were determined by the method of Thompson and Siiteri, using human placental microsomes and [1 beta,2 beta-(3)H]testosterone as the labeled substrate. All the compounds were also tested on 17 alpha-hydroxylase/C17,20-lyase (P450 17), an enzyme of therapeutic interest for the treatment of prostatic diseases. The goal to find new potent inhibitors of aromatase was reached with the xanthone derivatives 22d,e (IC(50) values 43 and 40 nM, respectively), which exceeded the potency of the known reference drug fadrozole and also showed high selectivity with respect to P450 17. Moreover, compounds 22g-i based on the same xanthonic nucleus showed fairly high potency as P450 17 inhibitors (IC(50) values 220, 130, and 42 nM, respectively). Thus, they might be new leads for the development of drug candidates for androgen-dependent diseases.

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The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multitarget strategies to combat causes and symptoms. We therefore designed, synthesized, and tested new hybrid molecules linking a benzofuran ring to a N-methyl- N-benzylamine through a heptyloxy chain, affording a series of potential multifunctional drugs for AD. The cholinesterase inhibitory activity was extended to the inhibition of Abeta fibril formation for 1, 3, and 5. Compound 3 showed an additional neuroprotective effect.

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.

Phytoestrogens represent a diverse group of non-steroidal natural products, which seem to have some oestrogenic effects and are often marketed as food supplements. Population exposed to phytoestrogens is potentially increasing, in part because an unfavourable risk-benefit profile of Hormone Replacement Therapy (HRT) for prolonged treatments (e.g., osteoporosis prevention) highlighted by the publication of the Women Health Initiative (WHI) trial in 2002, but also because many post-menopausal women often perceived phytoestrogens in food supplements as a safer alternative than HRT. Despite of increasing preclinical and clinical studies in the past decade, appealing evidence is still lacking to support the overall positive risk-benefit profile of phytoestrogens. Their status as food supplements seems to discourage studies to obtain new evidence, and the chance to buy them by user’s initiative make it difficult to survey their prevalence and pattern of use. The aim of the present review is to: (a) outline the clinical scenario underlying the increased interest on phytoestrogens, by overviewing the evolution of the evidence on HRT and its main therapeutic goals (e.g., menopausal symptoms relief, chemoprevention, osteoporosis prevention); (b) address the chemical and pharmacological features (e.g. chemical structure, botanical sources, mechanism of action) of the main compounds (e.g., isoflavones, lignans, coumestans); (c) describe the clinical evidence on potential therapeutic applications; (d) put available evidence on their riskbenefit profile in a regulatory perspective, in light of the recent regulation on health claims of food supplements.

Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.

The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.