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Novel classes of CB2 agonists based on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over CB1. A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing \( r_{ncv}^2 = 0.84 \), \( r_{cv}^2 = ~0.619 \), SEE = 0.369, and \( r_{pred}^2 = 0.75 \). The study provides useful suggestions for the synthesis of new selective analogues with improved affinity.

The synthesis and in vitro antiplatelet activity significant data of coumarin derivatives 5i-x and quinolin-2(1H)-one derivatives 22a,b, as well as the corresponding structure-activity relationships are described. The recently reported 8-methyl-4-(1-piperazinyl)-7-(3-pyridylmethoxy)coumarin 5f and its potent 7-(2-morpholinoethoxy)-substituted new analogue 5u were notably more effective inhibitors of pure human platelet PDE3 than milrinone and cilostazol: these data were related, through a molecular modeling study, with the molecular interactions of the four compounds with the human PDE3A catalytic site.

In this paper, we are presenting a quantitative-structure–activity relationship (QSAR) study performed on 21 selective A 1 adenosine receptor agonists plus the endogenous substrate, adenosine, so as to identify those predictors which play a key role in describing the binding of the ligand with the A 1 receptor. A large number of molecular descriptors plus a calculated receptor–agonist binding energy and atomic charges were taken into account to derive different QSAR models, using different regression techniques. The results obtained both with linear and nonlinear approaches converge to the selection of the same informative parameters, highlighting the correlation of these descriptors with the biological Response. The evaluation ‘a priori’ of these predictors could therefore represent a useful tool in the screening of large libraries of compounds and in the rational design of new selective agonists.

The pH-dependent distribution profiles of a series of pyridin-2(1H)-one analogs of the inotropic/vasodilator agent milrinone, determined in 1-octanol/water (and for a number of them also in chloroform–water) using a pH-metric technique, showed that partition coefficients of the neutral forms (log PN) significantly encode for 2-pyridone/2-hydroxypyridine tautomerism. A comparison between experimental and calculated log P (CLOG P) values indicated that electron-withdrawing substituents, at the C(6) position, and to a lesser extent at the C(3) and C(5) positions, push up log Ps toward the values of the more lipophilic 2-hydroxypyridine tautomers. RP-HPLC parameters ( log k ′ w ) carry for large part similar information related to tautomerism-dependent lipophilicity, but they were also found to reasonably correlate with the solute molar volumes (r2 = 0.75). Investigating the implications of ionization and partition properties in modulating the in vitro cardiotonic activity of the examined compounds revealed that a high fraction of the neutral species at physiological pH, predominantly in the more polar pyridone (OX) tautomer, increases the positive inotropic potency.

A series of 2,1,3- and 1,2,4-benzothiadiazine derivatives (BTDs) were synthesized and evaluated for their inhibitory activity versus enzymatic isoforms PDE3, PDE4 and PDE7. The compounds characterized by the 3,5-di-tert-butyl-4-hydroxybenzyl moiety at N1 position of 2,1,3-benzothiadiazine core (8, 13, 18), were found active and selective at micromolar level versus PDE4 and could be studied as new leads for the treatment of asthma and COPD (Chronic Obstructive Pulmonary Disease). The antioxidant activity evaluation on the same compounds highlighted 13 as the most significative. Molecular modelling studies gave further support to biological results and suggested targeted modifications so as to improve their potency.

Synthesis and biological evaluation of a new class of 1-aryl-4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives are reported. A preliminary cellular assay system using the tumor cell line A431 responding to epidermal growth factor (EGF) for its growth, shows that the new compounds are potent inhibitors of cell growth. The inhibition of tumor cell proliferation is not associated with blockage of EGF receptor (EGFR), but substantially due to the interference with the signalling pathway at the level of Src tyrosine kinase and at the level of the downstream effector signal mitogen activated protein kinases (MAPKs), ERK1-2.

Two mechanisms are responsible for the positive inotropic effect of the cardiotonic drug milrinone, i.e., inhibition of type III cAMP phosphodiesterase (PDE III), and displacement of endogenous adenosine from A(1) inhibitory receptor. Since PDE III inhibition may increase the likelihood of cardiac arrhythmias by increasing cAMP content, our attention focused on the synthesis of new compounds with more pronounced characteristics as adenosine antagonists. In this work, four new milrinone analogues were studied, in comparison with the parent drug, for their effects on the contractility of guinea pig isolated atrial preparations, their ability to antagonize endogenous adenosine at the level of A(1) receptor, and to inhibit the activity of PDE III partially purified from guinea pig heart. The new compounds present various chemical substitutions with respect to the parent drug: in compounds SF397 (methyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF399 (benzyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate), the 4-pyridil moiety of milrinone was replaced with a methoxycarbonyl and a benzyloxycarbonyl group, respectively; the same structural modifications were also associated with the replacement of the cyano-group in 5-position with an acetyl group in compounds SF416 (methyl 5-acetyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF419 (benzyl 5-acetyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate). All the new compounds had a marked positive inotropic effect, most of them also being more active and more potent than milrinone. When their affinity for A(1) receptor was assessed as the displacement of [(3)H] 8-cyclopentyl-1,3-dipropylxanthine ([(3)H]DPCPX) from cardiac membranes, SF397 and SF399 showed affinity (K(i) of about 600 nM) similar to that of milrinone (K(i) 550 nM). By contrast, SF416 and SF419 had very low (K(i) of about 10000 nM) or scarce (K(i) of about 2000 nM) anti-adenosine component, respectively. All the new compounds inhibited PDE III activity, their K(i) values proceeding in the following order: milrinone (3.80 microM)SF397 (7.00 microM)SF399 (8.80 microM)SF416 (35.00 microM) SF419(155.00 microM). To better characterize the mechanisms responsible for the positive inotropic response of the new compounds, we also investigated the effects of new analogues on some systems (ATP-dependent Ca(2+) uptake, Ca(2+)ATPase, Na(+)/K(+)ATPase, Na(+)/Ca(2+) exchange carrier) or a receptor (beta-adrenoceptor) mainly involved in the control of cardiac contractility. None of the tested compounds inhibited enzyme or transport systems; however, SF397, SF399 and SF416, although to different extents, had a direct beta-adrenergic action. Indications about structure-activity relationships are tentatively discussed, in order to obtain useful information for the design of new analogues with better pharmacological profiles.

Adenosine is a naturally occurring purine nucleoside that has a wide variety of well-documented regulatory functions and physiological roles. Selective activation of the adenosine A1 receptor has drawn attention in drug discovery for the therapeutic effects on neural and cardiovascular disorders. We have developed a model of the human A1 adenosine receptor using bovine rhodopsin as a template. A flexible docking approach has been subsequently carried out for evaluating the molecular interactions of twenty-one selective A1 agonists with the receptor model. The results of these studies are consistent with mutational and biochemical data. In particular, they highlight a wide hydrogen-bonding network between the nucleoside portion of the ligands and the A1 receptor as well as key amino acids for hydrophobic interactions with the different N6-groups of the agonists. The models presented here provide a detailed molecular map for the selective stimulation of the adenosine A1 receptor subtype and a steady basis for the rational design of new A1 selective ligands.

In PUVA (Psoralen plus UVA) chemotherapy 8-methoxypsoralen is the most widely used compound, although its efficacy is endowed with undesired side effects. In order to have an evident anti-proliferative activity with a reduced phototoxicity, many linear and angular derivatives have been synthesised. In this paper we describe a QSAR study in which, by means of the neural networks methodology, a useful model for predicting biological activity, expressed as ID50 (the UVA dose that reduces to 50% the DNA synthesis in Ehrlich cells), has been derived. A decision tree that is able to discriminate between active and inactive compounds has been built based on recursive partitioning. The study shows the key structural features responsible for the activity and could be a helpful tool in the rational design of new, less toxic, photochemotherapeuthic agents.

A number of 4-dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1 H -pyrazol-4-yl)butan-1-ols 2a – n were synthesized and tested in vivo for anti-inflammatory and analgesic activities and in vitro for platelet anti-aggregating activity. Dimethylaminoderivatives 2b , e , g showed good analgesic activity; almost all of them had strong platelet anti-aggregating properties at a final concentration of 1×10 −3 M; pyrazoles 2c , d , f – h showed weak anti-inflammatory activity.

Furocoumarins are an important class of compounds for photochemotherapy used in the treatment of numerous diseases characterised by hyperproliferative conditions. Their photosensitising activity has been related to the ability to form covalent linkage with the pyrimidine bases of DNA upon UV-A irradiation. Using the published experimental data of the 3D-structure of the furan-side monoadduct between the 4′-(hydroxymethyl)-4,5′,8-trimethylpsoralen and the DNA oligonucleotide d(GCGTACGC)2 as starting point, a computational procedure to study the dark intercalation complexes by molecular dynamics was built and then preliminary validated on another psoralen. This docking procedure provides a tool to better understand the mechanism of the DNA-intercalation of these linear furocoumarins and it can be useful in the design of new photochemotherapeutic agents with an improved therapeutic profile.

1. 1. Two new milrinone analogs, 3-acetyl-6-phenyl-2(IH)-pyridone (SF 348) and 3-acetyl-7-methyl-7,8-dihydro-2,5(1H, 6H) quinolinone (SF 349), increase the contractile activity of spontaneously beating and electrically driven atria isolated from reserpine-treated guinea-pigs. 2. 2. Propranolol 0.1 μM drastically inhibits the contractile effect of SF 348, whereas that of SF 349 is unaffected. Preincubation of the atria with adenosine-deaminase suppresses the cardiac activity of SF 349, but does not affect that of SF 348. 3. 3. SF 349 competitively antagonizes the negative inotropic effect induced by N6-(R-phenylisopropyl)-adenosine (R-PIA) and displaces N 6 - cyclohexyl [ 3 h]- adenosine (3H-CHA) from its binding sites to A1 receptors in the guinea-pig heart. 4. 4. The positive inotropic effect of SF 348 is largely sustained by activation of β-adrenoceptors, whereas SF 349 acts by displacing endogenous adenosine from its inhibitory (A1) receptors in the atria.

A series of carbinols 3a-f was prepared starting from methanols 1a-f via oxidation with pyridinium chlorochromate to aldehydes 2a-f, followed by a Grignard reaction of the latter. Reaction of 3a-f with ω-chloroalkyldialkylamine hydrochlorides afforded a series of aminoether derivatives 4g-t. Compounds 4i,m-p,s showed a good analgesic activity in the acetic acid writhing test in mice. Moreover, compounds 4h,1,s exhibited a moderate anti-inflammatory activity in the carrageenan-induced edema assay in rats.

The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.

Single-crystal X-ray work has been carried out on the 2-benzyl-5-cyano-1,6-dihydro-6-oxo-3-methoxycarbonyl pyridine compound 1f. It crystallizes in the triclinic system space group P 1 . Minimum energy conformations of 2-(alkyl or arylalkyl) 5-cyano-1,6-dihydro-6-oxo-3-pyridine carboxylates showing different biological activity have been calculated by the semiempirical MNDO and AM1 methods. A most critical factor for the different inotropic activities (positive or negative) of compounds 1a–1f seems to be related to the location and the steric requirements of a ‘pocket’ in the receptor boundary that limit the size of the substituent at position 2.

The synthesis of ethyl or methyl esters of 2-substituted 5-acetyl-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids 2a-d, f and 5 by reaction of sodium acetoacetamide with ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates and ethyl 2-ethoxymethylene-4,4,4-trifluoro-3-oxobutanoate, respectively, has been described. These esters routinely gave the corresponding carboxylic acids by alkaline hydrolysis followed by acidification. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria and on contractile activity of electrically-driven left atrium from reserpinetreated guinea pigs. Among the tested compounds, ethyl 5-acetyl-1,6-dihydro-6-oxo-2-phenyl-3-pyridinecarboxylate was found to be more potent and more effective than milrinone as a positive inotropic agent, while only marginally affecting the frequency rate.

The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dimethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried out by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalkanoates with 1,1-dimethylguanidine, is described. The above esters were hydrolyzed to the relative carboxylic acids 21-30, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Their effects were compared to those induced by milrinone in both atria preparations. Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid) was the most effective positive inotropic agent, while the corresponding methyl ester 17 reduced both the contractile force and the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be involved in the contractile activity of compound 28. By contrast, compound 17 might be partial agonist at the purinergic inhibitory (A1) receptor. X-ray analysis carried out on 17 and 28 and molecular modeling investigations extended also to related derivatives allowed a possible rationalization between structure and inotropic activity for this series of compounds.

The synthesis of amides 3 and 4 starting from (1-phenyl-1H-indazol-4-yl)acetic and [(1-phenyl-1H-indazol-4-yl)oxy]acetic acids, respectively, as well as of 2-(1-phenyl-1H-indazol-4-yl)ethanamines 5 starting from 3, is described. Moreover, a number of 2-[(1-phenyl-1H-indazol-4-yl)oxy]ethanamines 7 and 3-[(1-phenyl-1H-indazol-4-yl)oxy]propanamines 8 were prepared starting from 1-phenyl-1H-indazol-4-ol. Some compounds 3, 4 and 7 showed an appreciable analgesic activity in mice, whereas compounds 4 were moderately active as antiinflammatory agents in rats. Some compounds 3, 4, 5, 7 and 8 showed also local anesthetic and a weak antipyretic activity in mice and rats, respectively.

The synthesis of ethyl or methyl 6-substituted 3-(benzoylamino)-2-oxo-2H-pyran-5-carboxylates 2 and 3-(benzoylamino)-7,8-dihydro-2H-1-benzopyran-2,5(6H)-diones 4 by reaction of hippuric acid in acetic anhydride with ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates and 2-dimethylaminomethylene-1,3-cyclohexanediones, respectively, is described. Some compounds 2 and 4 showed a strong local anesthetic activity in mice and a platelet antiaggregating activity in vitro comparable to that of acetylsalicylic acid, as well as moderate analgesic, antiinflammatory and antiarrhythmic activities in rats and mice.

Reaction of methyl 4-methoxy-2-dimethylaminomethylene-3-oxobutanoate with arylhydrazines gave methyl 1-aryl-5-(methoxymethyl)-1H-pyrazole-4-carboxylates 1 in high yields. Esters 1 were hydrolyzed to the relative carboxylic acids, which were converted by heating to 1-aryl-5-(methoxymethyl)-1H-pyrazoles 3 in good yields. Reaction of 3 with hydrobromic acid afforded the intermediate 1-aryl-5-(bromomethyl)-1H-pyrazoles, which were converted with potassium cyanide to 1-aryl-1H-pyrazole-5- acetonitriles, whose hydrolysis gave the required 1-aryl-1H-pyrazole-5-acetic acids. Some acids 5 showed a strong antiinflammatory and analgesic activity in rats and mice, respectively, as well as moderate antipyretic and in vito platelet antiaggregating effects.

Convenient synthesis of 3-acyl-2H-furo[2,3-h]-1-benzopyran-2-ones, esters of 2-oxo-2H-furo[2,3-h]-1-benzopyran-3-carboxylic acid and 2H-furo[2,3-h]-1-benzopyran-3-carboxamides was accomplished via aromatization of the adducts obtained by a reaction between (E)-5-dimethyl-aminomethylene-6,7-dihydrobenzofuran-4(5H)-one and the appropriate acylacetate or dialkyl malonate. These compounds are angelicin derivatives which were prepared with the aim of obtaining intrinsically monofunctional drugs for photochemotherapy, with only one photoreactive site in their molecule. The new angelicins appear to be free of the known phototoxicity of furocoumarins on the skin and at a genetic level. The 3-carboxylic esters showed significant antiproliferative activity in Ehrlich ascites cells and T2 bacteriophage; the other derivatives were only slightly effective. The features of these compounds are such that they represent a new model for non-toxic agents for photochemotherapy.

A series of angelicin heteroanalogues, in which the furan was replaced by thiophene or a 1-substituted pyrazole moiety, was synthesised in order to obtain potential therapeutic agents with antiproliferative and/or other biological activities. In general, the antiproliferative activity of the new thioangelicin, tested in different biological substrates, appeared to be higher than that of the angelicin, the natural parent compound, but lower than that of 8-MOP, the furocoumarin ordinarily used in PUVA therapy and photopheresis. Thioangelicin 6 induced strong inhibition of T2 bacteriophage infectivity and was able to significantly repress the DNA synthesis in Ehrlich ascites cells and the clonal growth in HeLa cells. The pyrazolocoumarins did not show any noticeable effect upon UVA irradiation in all the biological systems considered. All the new angelicin heteroanalogues appeared to be free of the known phototoxicity of furocoumarins on the skin. The pyrazolocoumarins have also been tested as anti-inflammatory, analgesic, antipyretic, local anaesthetic, anti-arrhythmic and platelet anti-aggregating agents by standard procedures. In this class of derivatives, 10a showed good anti-inflammatory and antipyretic properties, while 9a and 11a showed significant local anaesthetic activity.

A series of milrinone analogues, namely 6-substituted 3-acetyl-5-acylpyridin-2(1 H )-ones 4a–c , e , f and 7-substituted or unsubstituted 3-acetyl-7,8-dihydro-2,5(1 H ,6 H )-quinolinediones 4g–j , in which the cyano group was replaced by the acetyl function, was prepared. In a preliminary pharmacological investigation on spontaneously beating atria from reserpine-treated guinea-pigs, all new compounds did not induce any inotropic effect equivalent or higher than that of the milrinone chosen as the reference compound. In order to rationalise how the structure modifications influence the activity and the selectivity of the title compounds, a computational study has been performed. The important role of the substituents in positions-3 and -6 on the pyridone nucleus has been highlighted.

A series of azole derivatives, isoxazole or pyrimidine analogues of the antifungal drug bifonazole, were synthesized and testedin vitro against representative human pathogenic fungi ( Candida albicans , Cryptococcus neoformans and Aspergillus fumigatus ).They were also evaluated as antibacterial agents against Staphylococcus aureus and Salmonella spp. Only 5-(imidazol-1-yl-phenyl-methyl)-2,4-diphenyl-pyrimidine 7c showed weak antimicrobial activity (MIC=66 M) against C . albicans , C . neoformans and S . aureus . Results of biological tests proved, therefore, that replacement of the biphenyl portion of the bifonazole with aphenylisoxazolyl or phenylpyrimidinyl moiety is not profitable for antimicrobial properties. © 2001 Elsevier Science S.A. Allrights reserved. Keywords :Azole derivatives; Antifungal agents; Bifonazole analogues 1. Introduction The continuously changing epidemiology of invasivefungal infections results in the need for an expandedarmamentarium of antifungal therapies. On the otherhand, the increased use of antimicrobial agents in re-cent years has caused the development of resistance toavailable drugs. For these reasons, a constant efforttoward the synthesis of new antifungal agents has beenmade in the last few years.In particular, the class of azoles (imidazole and tria-zole derivatives) has supplied many effective antifungaldrugs currently in clinical use, and newer azoles withexpanded spectrum of activity are at the moment incontinuous development [1].After the discovery of bifonazole (

The synthesis of a new family of A1-adenosine receptor (A1AR) ligands 3a–n has been performed in a straightforward way. Affinity data at A1AR, A2AAR and A3AR in bovine membranes show that these new compounds bind the A1AR in a selective way over A2AAR and A3AR and one of them (3j) presents a very high affinity, probably due to the phenethylamine substituent at C-4.

A number of new furo and thienoquinolinones carrying an electron-withdrawing function or unsubstituted at the position 3 were synthesized in order to obtain new potential photochemotherapeutic agents with increased antiproliferative activity and decreased toxic side effects. Our interest in studying the SAR of these derivatives also prompted us to investigate the influence of N-methylation on biological activity, by preparing N-methyl derivatives. The antiproliferative activity of all the newly synthesized compounds was evaluated and compared to 8-methoxypsoralen (8-MOP), the drug widely used in PUVA-therapy. The 3-unsubstituted thienoquinolinones were generally the most potent derivatives, followed by the furo-analogues. In particular, the unsubstituted thieno[2,3-h]quinoline-2(1H)one showed the highest activity in T2 bacteriophage, HeLa cells and Ehrlich cells tests. All the compounds, assayed on Escherichia coli WP2 TM9, showed a similar mutagenic activity, very close to that of 8-MOP. Except for 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylic acid, which appeared to be very effective, all compounds generated singlet oxygen to slightly larger amounts when compared to 8-MOP. The N-methyl analogues only induced moderate skin erythemas on albino guinea pigs, while all other derivatives appeared to be entirely inactive. On the basis of these results, the unsubstituted thieno[2,3h]quinoline 2(1H)one seems to be the most interesting potential drug for PUVA photochemotherapy and photopheresis.

Novel classes of cannabinoid 2 receptor (CB2) agonists based on 1,2,3,4-tetrahydropyrrolo[3,4-b]indole and benzimidazole scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over cannabinoid 1 receptor (CB1). A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, initially on each series of agonists, and subsequently on all compounds together, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing cross-validated r2 (rcv2) = 0.680, non cross-validated r2 (rncv2) = 0.97 and test set \( {{\hbox{r}}^2}\left( {{\hbox{r}}_{\rm{pred}}^2} \right) = 0.{93} \). The study provides useful suggestions for the design of new analogues with improved affinity.

Acylthiocarbamates (ATCs) have been identified as a class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was used to identify the most important features impacting ATC antiretroviral activity. The CoMSIA model proved to be the more predictive, with r 2 ncv = 0.89, r cv 2 = 0.38, standard error of estimate (SEE) = 0.494, F = 84, and r 2 pred = 0.81. The results of these studies will be useful in designing new ATCs with improved potency, also against clinically relevant resistant mutants.

Pyrazolo[3,4-b]pyridines have been recently presented as a novel class of adenosine A1 receptor antagonists. Depending on substitutions on some key positions of their scaffold they show selectivity towards A1, A2A or A3 receptors, which results in a variety of therapeutic potentialities of these ligands. In this work, we present a QSAR study on these analogues as antagonists for adenosine A1 receptors. Using the MOE software we identified a pool of descriptors that numerically describes the ligand features impacting the affinity at adenosine A1 receptors. The obtained information is useful to understand the main structural features that strongly correlate with the A1 antagonism in this class of compounds and will be used for the rational design of more potent and selective pyrazolo[3,4-b]pyridine derivatives.

Sixty-eight new substituted pyrazolo[3,4-b]pyridine derivatives were synthesized and tested for enriching a library of active A 1 adenosine receptor (AR) antagonists belonging to the same class. These compounds were also used as an external test set to check the reliability of a 3D QSAR model recently reported by us. To investigate the binding mode of pyrazolopyridine derivatives, a model of the bovine A 1 AR (bA 1 AR) was developed by a novel homology modeling approach and used to evaluate the main interactions of the ligands with the receptor through docking studies. Results suggest important interactions of the ligands mainly with L3.33(88), T3.36(91), Q3.37(92) and H6.52(251), in agreement with mutagenesis data. The racemic mixture of the most active compound was separated into the corresponding enantiomers which showed a bA 1 AR affinity in the nanomolar range, with the R enantiomer sevenfold more active than the S enantiomer, according to results derived from calculations on the receptor model. Analysis of the bovine/human A 1 AR affinity profile of ligands supported the hypothesis that such receptors should be characterized by a different size of their binding site, responsible for the different affinity of the antagonists.

The synthesis of new 4-amino substituted pyrazolo[3,4-d]pyrimidines along with their activity in cell-free enzymatic assays on Src and Abl tyrosine kinases is reported. Some compounds emerged as good dual inhibitors of the two enzymes, showed antiproliferative effects on two Bcr-Abl positive leukemia cell lines K-562 and KU-812, and induced apoptosis, as demonstrated by the PARP assay. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction with both Src and Abl.

Thiocarbamates (TCs) have been recently identified as a new class of potent non-nucleoside HIV-1 Reverse Transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses, has been used to elucidate the atomic details of the RT/TC interactions and to identify the most important features impacting the TC antiretroviral activity. The CoMFA model resulted to be the more predictive, and gave r(2)=0.93, r(cv)(2)=0.53, SEE=0.292, F=180, and r(test)(2)=0.70. The 3D-QSAR field contributions and the structural features of the RT binding site showed a good correlation. These studies will be useful to design new TCs with improved potency also against clinically relevant resistant mutants.

In the last few years, much effort has been directed towards the synthesis of selective adenosine receptor (AR) antagonists since they are attractive tools for pharmacological intervention in many pathophysiological conditions. During our studies aimed at obtaining new nonclassical adenosine antagonists devoid of phosphodiesterase (PDE) inhibition, a series of 2-pyridones and 2,5-quinolinediones (3a–f, 5a–f, 6a,c–f) has been synthesized as potential AR ligands. Binding affinities of the new compounds were determined for bovine and human adenosine A1, A2A, and A3 receptors. Compound 5f showed good affinity (K i = 7.8 μM) towards human A1AR but no selectivity (K i = 7.0 μM) towards human A2AAR, whereas compound 6f showed more affinity towards human A2A (K i = 16 μM) than A1 receptor (percentage inhibition at 10 μM concentration = 11). In the 1–100 μM range, the new compounds did not inhibit cardiac PDE3 activity at all. Molecular modeling studies carried out on 5f and 6f support the pharmacological results and suggest 6f as a potential lead compound selective towards A2AAR.

In order to elucidate the structural requirements for human CB(1) receptor antagonism, 78 antagonists belonging to five different chemical classes were selected from the literature and docked into the receptor binding site, built by homology modeling techniques. To further explore the structure-activity relationships within the considered chemical classes, a pharmacophore model and a QSAR analysis were developed. In a first step five alignments, one for each group of compounds were generated. All of them were then submitted to a MOE pharmacophore search in order to obtain a final pharmacophore model representative of the whole dataset which was used to elaborate the following 3D-QSAR analysis, by means of the CoMFA methodology. The results of these investigations are expected to be useful in the process of design and development of new potent CB(1) antagonists.

The X-ray structural characterization of ethyl 5-cyano-1,6-dihydro-2-isopropyl-6-oxo-3-pyridine carboxylate is reported. Its solid state conformation has been compared with that of ethyl 2-methyl- and 2- tert -butyl-5-cyano-1,6-dihydro-6-oxo-3-pyridine carboxylate and with the results of a quantum chemical analysis at MNDO level in order to study the structure-activity relationship. Theoretical data indicate that the 2-substituent appears to be primarily responsible for the potencies and the different inotropic activities (positive or negative) of compounds 1–3 .

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with N-C-N dinucleophiles such as guanidine, acetamidine or benzamidine afforded in high yields the relative esters of 4-substituted 2-amino-, 2-methyl- or 2-phenyl-5-pyrimidinecarboxylic acids, respectively. These esters were hydrolyzed to the corresponding carboxylic acids, which were converted by heating to 4-substituted 2-pyrimidinamines, 2-methyl or 2-phenylpyrimidines, respectively, generally in excellent yields. The 4-unsubstituted ethyl 2-amino-, 2-methyl- and 2-phenyl-5-pyrimidinecarboxylates were obtained in moderate yields by reaction of the above dinucleophiles with ethyl 2,2-diformylacetate. These esters were hydrolyzed and the corresponding acids (with the exception of the 2-methyl derivative) were decarboxylated to give 2-pyrimidinamine and 2-phenylpyrimidine in satisfactory yields.

Among cannabinoid type-1 (CB1) receptor antagonists, those developed around the 1,5-diarylpyrazole scaffold of rimonabant (Acomplia™) are the most extensively investigated. In recent years, many SAR and QSAR reports on this topic have been published, focusing on the substitution and orientation of the N1 and C5 aryl functionalities and on the substituents at the 3-carboxamide position. In this context, the purpose of our study was to design and synthesize a set of 1-(2,4-dichlorophenyl)-5-arylpyrazoles strictly related to rimonabant, but with the hydrazide/amide group shifted from position 3 to position 4 of the pyrazole scaffold. The synthesized compounds were evaluated in vitro for their affinity on human CB1 and CB2 (cannabinoid type-2) receptors. Computational studies, performed both in the design step and after biological assays, contributed to rationalize the obtained results in terms of specific molecular interactions between antagonists and the human CB1 receptor.

A facile stereoselective synthesis of Knoevenagel-type compounds 8 and 9 was accomplished through a one-pot two-step procedure. The reaction of ethylenethiourea ( 1) and ethyleneurea ( 2) with benzoyl chloride- N, N-dimethylformamide complex in N, N-dimethylformamide gave the corresponding isolable ternary N-methyleniminium chlorides 3 and 4, along with benzoic acid ( 5) as a byproduct. Hydrolysis of salts 3 and 4 yielded the N-formyl derivatives 6 and 7, thus confirming the N-methyleniminium structure. Salts 3 and 4 condensed in situ at 120 °C with a variety of acyclic active methylene reagents Y-CH 2 -Z (Y = or ≠ Z), in the presence of 5 (Procedure A) or of 5 and triethylamine (1.5 equiv) (Procedure B), afforded α,β-unsaturated compounds 8 and 9. The overall yields ranged from poor to good. Mechanistic hypotheses concerning the formation of 3 and 4 and the origin of the stereoselectivity are also discussed.

We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.