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 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.

Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives.

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.

Acetylcholinesterase inhibitors: SAR and kinetic studies on omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl derivatives.

In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.

A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase.

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.

Selective cardiodepressant activity of fluodipine, a fluorenone-1,4-dihydropyridine derivative.

The effect of the dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl-4-(fluorenon-4-yl)pyridine-3,5-dicarboxyl ic acid diallyl ester (fluodipine) was studied in vitro in different rabbit, rat and guinea pig preparations and in vivo in the rabbit in order to characterize its pharmacological profile at cardiac and at vascular sites. Compared to nifedipine, fluodipine showed a similar cardiodepressant activity, and a much lower inhibitory activity on vascular contraction. The highest tissue selectivity was observed in guinea pig preparations: fluodipine was about 2-3 times more effective than nifedipine on chronotropism and inotropism in isolated atria, and about 150 times less effective on aortic strip contraction. Accordingly, fluodipine (i) showed high-affinity binding to guinea pig ventricular L-type cardiac Ca2+ channels (Ki=2.57 nM), (ii) was about 80 times less effective than nifedipine to inhibit Ca2+ influx in vascular smooth muscle cells and (iii) induced a significant reduction of heart rate in the anesthetized rabbit (ID25=8.5 mg kg(-1), i.v.) without affecting the blood pressure up to 20 mg kg(-1), whereas nifedipine showed a significant hypotensive effect at very low doses (ID25=0.18 mg kg(-1), i.v.). The pacemaker current If of rabbit sino-atrial node myocytes was not affected by fluodipine. These findings demonstrate that fluodipine exerts selective cardiodepressant activity, likely due to a higher affinity for cardiac than for vascular Ca2+ channels.

Bivalent ligand type beta-adrenolytics related to practolol.

The synthesis and pharmacological evaluation of a number of symmetrical bivalent ligand type beta-adrenolytics related to practolol are reported. The best results have been observed with N,N'-bis[3-[2-hydroxy-3-[1-methylethyl)amino]propoxy]phenyl] ethanediamide.

SAR studies in the field of Ca-antagonists: 2-substituted 1,4-dihydropyridines with a xanthone backbone.

A series of 2-substituted 1,4-dihydropyridines with a xanthone backbone was prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties.

Synthesis of a series of Homopterocarpane derivatives with potential antitumor and anti-AIDS activity.

The synthesis of a series of derivatives related to (+/-) cis 6a, 12a-dihydro-6H,7H-[1]-benzopyrano-[4,3-b]-[1]-benzopyran (Homopterocarpane) is described. The synthesized derivatives have been tested at National Cancer Institute in its in vitro anti-cancer and anti-AIDS screening programs. The synthesized compounds are inactive in anti-HIV assay, while some show a GI50 < 100 microM (and < 50 microM in several cell lines) in NCI antitumor screening.

Some new prazosin-like derivatives.

The preparation of a number of prazosin-like derivatives is reported. The new derivatives differ from the parent compound for the 2-side-chain which is represented by peculiar fragments of butyrophenone neuroleptics. The results of the pharmacological evaluation are also reported.

Design of multifunctional compounds for cardiovascular disease: from natural scaffolds to "classical" multitarget approach.

Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted.

Benzo-gamma-pyrone analogues of geiparvarin: synthesis and biological evaluation against B16 melanoma cells.

Chromone, flavone and xanthone analogues of geiparvarin (1) are described. Compounds 2a and 2b are more active in inhibiting the proliferation of F10 metastatic murine melanoma cells. In particular, 2a is 13 times more active at microM concentration after 48 h exposure.

Synthesis and pharmacological characterization of some benzazepinone derivatives.

A series of some benzazepinone derivatives were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties. For the compounds bearing well-known alpha-blocking fragments, the antagonist potency at postsynaptic alpha-adrenoceptors was assessed. The new compounds were less effective as bradycardic agents and calcium antagonists but show remarkable negative inotropic activity.

1,4-Dihydropyridines bearing a pharmacophoric fragment of lidoflazine.

A series of 1,4-dihydropyridines bearing a pharmacophoric fragment of lidoflazine was synthesized. The compounds were evaluated for inotropic, chronotropic, and calcium antagonist activities. All compounds behave as inotropic and chronotropic agents, except for compounds 4b, 5a, and 5b, which exhibit a rather weak calcium antagonism in vascular smooth muscle (like aorta). Compound 5b is about twofold more potent in decreasing both chronotropy and inotropy, while compound 5c is about fivefold more potent in decreasing inotropy than nifedipine. Moreover, compound 5b is the most potent calcium antagonist derivative of the series.

4-heterotricyclic substituted 1,4-dihydropyridines with a potent selective bradycardic effect.

A series of 4-heterotricyclic substituted 1,4-dihydropyridines were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties. The tested compounds are fairly good as calcium antagonists, but exert potent selective bradycardic effects.

Negative inotropic and chronotropic activity of calcium channel ligands possessing a xanthone 1,4-dihydropyridine backbone.

A series of xanthone 1,4-dihydropyridine derivatives were prepared. The compounds were evaluated for inotropic, chronotropic, and calcium antagonist properties.

Fluorenone and benzophenone 1,4-dihydropyridine derivatives with cardiodepressant activity.

A series of fluorenone and benzophenone 1,4-dihydropyridine derivatives were prepared. The compounds were evaluated for inotropic, chronotropic and calcium antagonist properties.

Antimicrotubular and cytotoxic activity of geiparvarin analogues, alone and in combination with paclitaxel.

Geiparvarin is an antiproliferative compound isolated from the leaves of Geijera parviflora, and may represent a new drug which targets tubulin. To better explore the potential use of this agent, we investigated the antimicrotubular and cytotoxic effects of new synthetic aromatic derivatives of geiparvarin. These drugs inhibited polymerization of microtubular protein, particularly when the assembly was induced by paclitaxel. The microtubular network organization of fibroblasts was altered more effectively by some drugs. Normal microtubule architecture completely disappeared when the cells were treated simultaneously with drugs and paclitaxel: microtubules depolymerized or were reorganized into bundles, in a similar but more disarrayed fashion than that observed after treatment with paclitaxel alone. Cytotoxicity studies showed a dose-dependent effect, whereas combined administration of drugs and paclitaxel increased cytotoxicity, more effectively in paclitaxel versus derivatives administration alone.

Geiparvarin and derivatives in combination with taxol: effect on microtubular organization in 3T3 fibroblasts.

Geiparvarin, a natural product that exhibits antiproliferative activity, inhibits the growth of various tumour cell lines with a mechanism of action so far unknown. Our preliminary findings showed that geiparvarin and some derivatives obtained from its conjugation with diethylstilboestrol and meso-hexestrol significantly inhibit taxol-induced in vitro polymerization of both tubulin and microtubular protein. In this study we investigated the effect of geiparvarin and of the oestrogen-combined derivatives on the cellular microtubular network of fibroblasts. Geiparvarin altered the microtubular organization of fibroblasts and strengthened the derangement of the microtubular pattern in cells exposed simultaneously to taxol. However, the microtubular network remained quite well organized in fibroblasts exposed to geiparvarin and preincubated with taxol, which in this case prevented the deranging effect of the former. The antimicrotubular activity of the oestrogen-combined derivatives was more similar to that of geiparvarin than to that of the oestrogens, and often this activity was stronger than that of each reference drug alone; the cytotoxic activity examined in the same experimental conditions generally confirmed the microscopic analysis.

Coumarin 1,4-dihydropyridine derivatives.

A series of 1,4-dihydropyridines bearing a coumarin moiety in 4-position was synthesized. The compounds were evaluated for inotropic, chronotropic and calcium antagonist activities. The replacement of the o-nitrophenyl moiety of nifedipine with a coumarin or phenylcoumarin system is accompanied by a decrease of the activity on myocardial and vascular parameters, but the synthesized compounds showed selective inhibiting effects on cardiac contractility and frequency.