Stilbene-pyridazinone hybrids: design, synthesis and in vitro antiplatelet activity screening.

A series of stilbene analogues, in which a phenyl ring was replaced by the pyridazin-3(2H)-one nucleus, was designed and synthesized to be explored as platelet aggregation inhibitors. The proposed stilbene-pyridazinone hybrids were successfully obtained from simple starting materials and by Wittig's reaction. Most of the target compounds displayed improved in vitro activity in comparison with the standard drug, resveratrol, highlighting as the most potent the analogues 10d and 10e, with inhibition percentages of 94.15 % at 100 µM and 100 % at 50 µM, respectively. The pharmacokinetic and toxicity (ADME/T) properties of the novel hybrids were also estimated with the SwissADME and ProTox-II web servers.

Novel Phthalazin-1(2H)-One Derivatives Displaying a Dithiocarbamate Moiety as Potential Anticancer Agents.

Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6-8, which display the dithiocarbamate scaffold at N2, and compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6-8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a-b, 9d, and 9g with IC50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.

Pyridazinones containing dithiocarbamoyl moieties as a new class of selective MAO-B inhibitors.

A novel class of potential MAO-B inhibitors was designed and synthesized in good yield by combining the pyridazinone moiety with the dithiocarbamate framework, two relevant pharmacophores for drug discovery. The biological results obtained for the different pyridazinone/dithiocarbamate hybrids (compounds 8-14) indicated that most of them reversibly and selectively inhibit the hMAO-B in vitro with IC50 values in the µM range and exhibit not significant cellular toxicity. The analogues 9a1, 11a1, 12a2, 12b1 and 12b2, which present the dithiocarbamate fragment derivatized with a piperidin-1-yl or pyrrolidin-1-yl group and placed at C3 or C4 of the diazine ring, were the most attractive compounds of these series. Molecular modeling studies were performed to analyze the binding mode to the enzyme and the structure activity relationships of the titled compounds, as well as to predict their drug-like properties.

Novel coumarin-pyridazine hybrids as selective MAO-B inhibitors for the Parkinson's disease therapy.

The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f). All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC50 values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC50 = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent. Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds.

2-Benzyl-5-meth-oxy-isoindoline-1,3-dione.

The title N-benzyl-phthalimide derivative, C16H13NO3, consists of two planar moieties, viz. the phthalimide system (r.m.s. deviation = 0.007 Å) and the phenyl ring, which make a dihedral angle of 84.7 (6)°. The meth-oxy group is almost coplanar with the phathalimide ring, as shown by the C-C-O-C torsion angle of -171.5 (2)°. In the crystal, the mol-ecules are self-assembled via non-classical C-H⋯O hydrogen bonds, forming a tape motif along [110].

5-[(tert-Butyl-diphenyl-sil-yloxy)meth-yl]pyridazin-3(2H)-one.

In the title compound, C21H24N2O2Si, a new pyridazin-3(2H)-one derivative, the carbonyl group of the heterocyclic ring and the O atom of the silyl ether are located on the same side of the pyridazinone ring and the C-C-O-Si torsion angle is -140.69 (17)°. In the crystal, mol-ecules are linked by pairs of strong N-H⋯O hydrogen bonds into centrosymmetric dimers with graph-set notation R 2 (2)(8). Weak C-H⋯π inter-actions are also observed.

Novel Pyridazin-3(2H)-one-Based Guanidine Derivatives as Potential DNA Minor Groove Binders with Anticancer Activity.

Novel aryl guanidinium analogues containing the pyridazin-3(2H)-one core were proposed as minor groove binders (MGBs) with the support of molecular docking studies. The target dicationic or monocationic compounds, which show the guanidium group at different positions of the pyridazinone moiety, were synthesized using the corresponding silyl-protected pyridazinones as key intermediates. Pyridazinone scaffolds were converted into the adequate bromoalkyl derivatives, which by reaction with N,N'-di-Boc-protected guanidine followed by acid hydrolysis provided the hydrochloride salts 1-14 in good yields. The ability of new pyridazin-3(2H)-one-based guanidines as DNA binders was studied by means of DNA UV-thermal denaturation experiments. Their antiproliferative activity was also explored in three cancer cell lines (NCI-H460, A2780, and MCF-7). Compounds 1-4 with a bis-guanidinium structure display a weak DNA binding affinity and exhibit a reasonable cellular viability inhibition percentage in the three cancer cell lines studied.

Synthesis and complete assignment of the 1H and 13C NMR spectra of 6-substituted and 2,6-disubstituted pyridazin-3(2H)-ones.

Several pyridazin-3(2H)-one derivatives were synthesized starting from alkyl furans using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of the synthetic strategy followed. For all pyridazinones reported, a complete assignment of the (1)H and (13)C NMR spectra using one- and two-dimensional NMR spectroscopic methods, which included NOE, DEPT, COSY, HSQC and HMBC experiments, was accomplished. Correlations between the chemical shifts of the heterocyclic ring atoms and substituents at N-2 and C-6 were analyzed.

The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models.

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.

New pyridazinone derivatives with vasorelaxant and platelet antiaggregatory activities.

New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds.

Complete assignment of the (1)H and (13)C NMR spectra of cis and trans isonucleoside derivatives of purine with a tetrahydropyran ring.

(1)H and (13)C NMR chemical shifts of cis and trans isonucleoside analogues of purine in which the furanose moiety is substituted by a tetrahydropyran ring were completely assigned using one- and two-dimensional NMR experiments that include NOE, DEPT, COSY and HSQC. The significant (1)H and (13)C NMR signals differentiating between the cis and trans stereoisomers were compared.

Recent advances in the synthesis of phthalazin-1(2H)-one core as a relevant pharmacophore in medicinal chemistry.

Phthalazin-1(2H)-one is a diazaheterobicycle found in a wide variety of synthetic molecules relevant to several branches of chemistry, including medicinal chemistry. The versatility of phthalazinone core in drug discovery has promoted the search for new synthetic methods to get access to differently substituted and functionalized derivatives. This review highlights the latest advances in synthesis of phthalazinone derivatives that have relevance to drug discovery processes, analyzing modifications of classical methodologies based on [4 + 2] two-component cyclocondensations as well as novel multicomponent approaches, mostly based on a [3 + 2+1] three-component strategy and very attractive not only because of its synthetic efficiency but also in the matter of environmental compatibility.

Novel compounds of hybrid structure pyridazinone-coumarin as potent inhibitors of platelet aggregation.

Aim: The current limitations of antiplatelet therapy promote the search for new antithrombotic agents. Here we describe novel platelet aggregation inhibitors that combine pyridazinone and coumarin scaffolds in their structure. Results: The target compounds were synthesized in good yield from maleic anhydride, following a multistep strategy. The in vitro studies demonstrated significant antiplatelet activity in many of these compounds, with IC50 values in the low micromolar range, revealing that the activity was affected by the substitution pattern of the two selected cores. Additional studies point out their effect as inhibitors of glycoprotein (Gp) IIb/IIIa activation. Conclusion: This novel hybrid structure can be considered a good prototype for the development of potent platelet aggregation inhibitors.

New QSAR combined strategy for the design of A1 adenosine receptor agonists.

Combined discriminant and regression analysis was carried out on a series of 167 A1 adenosine receptor agonists to identify the best linear and nonlinear models for the design of new compounds with a better biological profile. On the basis of the best linear discriminant analysis and both linear and nonlinear Multi Layer Perceptron neural networks regression, we have designed and synthesized 14 carbonucleoside analogues of adenosine. Their biological activities were predicted and experimentally measured to demonstrate the capability of our model to avoid the prediction of false positives. A good agreement was found between the calculated and observed biological activity.

ANN-QSAR model for selection of anticancer leads from structurally heterogeneous series of compounds.

Developing a model for predicting anticancer activity of any classes of organic compounds based on molecular structure is very important goal for medicinal chemist. Different molecular descriptors can be used to solve this problem. Stochastic molecular descriptors so-called the MARCH-INSIDE approach, shown to be very successful in drug design. Nevertheless, the structural diversity of compounds is so vast that we may need non-linear models such as artificial neural networks (ANN) instead of linear ones. SmartMLP-ANN analysis used to model the anticancer activity of organic compounds has shown high average accuracy of 93.79% (train performance) and predictability of 90.88% (validation performance) for the 8:3-MLP topology with different training and predicting series. This ANN model favourably compares with respect to a previous linear discriminant analysis (LDA) model [H. González-Díaz et al., J. Mol. Model 9 (2003) 395] that showed only 80.49% of accuracy and 79.34% of predictability. The present SmartMLP approach employed shorter training times of only 10h while previous models give accuracies of 70-89% only after 25-46 h of training. In order to illustrate the practical use of the model in bioorganic medicinal chemistry, we report the in silico prediction, and in vitro evaluation of six new synthetic tegafur analogues having IC(50) values in a broad range between 37.1 and 138 microgmL(-1) for leukemia (L1210/0) and human T-lymphocyte (Molt4/C8, CEM/0) cells. Theoretical predictions coincide very well with experimental results.

Synthesis and structure-activity relationship study of novel 3-heteroarylcoumarins based on pyridazine scaffold as selective MAO-B inhibitors.

Compounds of hybrid structure pyridazine-coumarin were discovered as potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B). These compounds were synthesized in good yield following a multistep approach based on Knoevenagel reaction and using as key intermediate pyridazinone 16, which was obtained from maleic anhydride and furan. Compounds 9b and 9d are the most active compounds of these series, with IC50 values in the sub-micromolar range, and lack of cytotoxic effects. Theoretical calculation of ADME properties also suggested a good pharmacokinetic profile for both compounds. Docking simulations provided insights into enzyme inhibitor interactions and allowed us to rationalize the observed structure-activity relationships (SARs).

Quantitative structure activity relationships as useful tools for the design of new adenosine receptor ligands. 1. Agonist.

In order to minimize expensive drug failures it is essential to determine the potential biological activity of new candidates as early as possible. In view of the large libraries of nucleoside analogues that are now being handled in organic synthesis, the identification of a drugs biological activity is advisable even before synthesis and this can be achieved using predictive biological activity methods. In this sense, computer aided rational drug design strategies like Quantitative Structure Activity Relationships (QSAR) or docking approaches have emerged as promising tools. Although a large number of in silico approaches have been described in the literature for the prediction of different biological activities, the use of traditional QSAR applications in the development of new agonist molecules with affinity toward adenosine receptors is scarce. This review attempts to summarize the current level of knowledge concerning computational affinity predictions for adenosine receptors using QSAR models based on knowledge of the agonist ligands. Several computational protocols and different 2D and 3D descriptors have been described in the literature for these targets, but more effort is still required in this area.

Radial distribution function descriptors: an alternative for predicting A2 A adenosine receptors agonists.

The Radial Distribution Function approach has been applied to the study of the A2 A adenosine receptors agonist effect of 29 adenosine analogues: N6- arylcarbamoyl, 2-arylalkynyl-N6 -arylcarbamoyl, and N6 -carboxamido derivatives. A model able to describe around 85% of the variance in the experimental activity was developed with the use of the mentioned approach. In contrast, no one of nine different approaches, including the use of Galvez Topological Charges indexes, BCUT, Geometrical, 2D autocorrelations, Topological, Randic Molecular profile, WHIM, 3D-MORSE and GETAWAY descriptors were able to explain more than 78% of the variance in the mentioned property with the same number of variables in the equation. Finally, the model support that the bulkiness and stereoselectivity play an important role in the affinity for this receptor in this kind of compounds.

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery.

Phthalazinones are an important kind of nitrogen atom containing heterocyclic compounds due to their synthetic and pharmacological versatility. This fused heterocycle system represents a common structural feature for many bioactive compounds showing a variety of pharmacological activities such as anticancer, anti-diabetic, anti-asthmatic, antihistaminic, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant or antimicrobial agents, which makes it an attractive scaffold for the design and development of new drugs. This review summarizes detailed and updated information, described in recent non-patent literature, about the most relevant pharmacological properties of phthalazinone derivatives, highlighting the application of this potent pharmacophore in drug discovery.

New platelet aggregation inhibitors based on pyridazinone moiety.

New series of pyridazinone derivatives (4, 5 and 6) were synthesized in good yields following a synthetic strategy based on singlet oxygen oxidation of alkyl furans, in which a suitable ß(α)-substituted γ-hydroxybutenolide (10 or 11) or a bicyclic lactone (12 or 13) was the key intermediate. The synthesized compounds were tested in vitro as antiplatelet agents and some of them (compounds 4b, 4d and 5b) exhibited potent inhibitory effects on collagen-induced platelet aggregation with IC50 values in the low µM range. Studies performed with the most active compound of these series (4b) demonstrated its lack of activity as inhibitor of platelet aggregation induced by other agonists as thrombin, ionomycin or U-46619 suggesting a selective action on the biochemical mechanisms triggered by collagen in the platelets.