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The article discusses a study on a two-step route, which is Mitsunobu followed by Schiff base reactions, to asymmetrically substituted pyridazinones from maleic hydrazide with 2-, 3-, or 4-pyridinecarboxaldehyde. Highlights include the reaction of maleic hydrazide with ethanolamine under Mitsunobu conditions, the use of ethanolamine when performing the Mitsunobu step, and hydrogen bonded dimers and close stacking of pyridazinone moieties.

Aim: The aim of this study is to provide a qualitative and quantitative explanation of the structure activity relationships with pharmacophore analysis and Quantitative Structure Activity Relationship (QSAR) studies of the compounds synthesized as acetylcholinesterase enzyme inhibitor by our research group. Material and Methods: Maestro 11.9 (Schrödinger, New York) was used for pharmacophore model studies. Pharmacophore analysis was performed for all compounds showing acetylcholine esterase inhibitory effect. For QSAR studies, various physicochemical parameters of these compounds were calculated using GaussView 5.0 and ChemDraw 15.0 programs. Regression analysis was performed by using these parameters and QSAR equation was obtained. Results: All compounds overlapped and hypotheses generated. The most appropriate pharmacophore model was created by comparing the hypothesis and activity results of the compounds. The analyses were performed using 8 different parameters for all compounds. R2 value of equation was found 1. Conclusion: The pharmacophore analysis and the QSAR equation are applicable for all compounds synthesized as acetylcholinasterase inhibitory and containing pyridazinon-2-ylacetohydrazide structure. Also, the estimated IC50 values can be calculated before the compounds are synthesized using the QSAR equation. [ABSTRACT FROM AUTHOR]

The parent compound (6-methyl-2,6 dihydro[1,2,4-triazino[4,3-b]indazol-3(4H)-one was prepared from reaction of ((1-Methyl-1H-indazol-3-yl)-hydrazine) with ethyl bromoacetate, then (41) new compounds were synthesized. The first compound (1) was synthesized from condensation of parent compound with 2-chloro benzaldehyde in basic medium, after that novel compounds was derived from chalcone (1). Five, six and seven member ring were produced from cyclized of α,β unsaturated system with several materials such as (malononitrile, ethyle cyanoacetate, 2-amino phenol, 2-amino thiophenol, phenylene diamine mercapto acetic acid, phenyl hydrazine, ect) to offered (1-15) derivatives. The pyridazine and pyridazinone compounds (17-20) were synthesized from treatment of parent compound with dimethyl amine, methyl amine, chloro acetyl chloride and formic acid, respectively while derivative (21) produced from reaction of (20) with urea by. Besides that, compound (19) was a good key to synthesize oxazol, thiazol, thiazine and hydrazino derivatives (22, 23, 24 and 25) respectively. Hydrazino derivative (25) was also used for synthesis (26-28) derivatives. In additional to that, derivative (2) was a worthy core and a key intermediate for the synthesis of several new fused heterocycles in this work. Acylation of amino group in (2) with acetic anhydride was gave (29), while (2) cyclized with chloroacetic acid or malononitrile aes affered (30, 31) respectively. On the other side, amino group of (2) underwent to reaction with phenylisothiocyanate, ethylacetoacetate, urea, thiourea, phenylisothiocyanate and formamide to produce (32, 33, 34, 35, 37 and 38). While when derivative (2) cyclized with ethyl chloroacetate led to formation (36). Compound (2) was cyclized under heating with formamide, formic acid to give pyrimidine and pyrimidinone derivatives (39, 40) respectively. Finally, in presence of ethanol and hydrochloric acid, derivative (33) underwent to ring closure to produce (41). The structures, of all synthesized compounds were confirmed by using spectroscopic analysis such as UV, FTIR, 1H-NMR and 13CNMR spectral. [ABSTRACT FROM AUTHOR]

This review article presents a systematic overview of approaches and reactivity data for 2(3H)-furanones, published from 1999 until 2018. [ABSTRACT FROM AUTHOR]

A series of small-molecular fluorescent probes based on nitrogen-fused pyridazinone scaffold were developed in this report. The design strategy involved two steps: 1) enhancing the electron-withdrawing ability of the acceptor by incorporating an N-heterocyclic aromatic ring (pyridine or pyrazine) at the C4 and C5 positions of the pyridazinone skeleton and 2) anchoring a triphenylphosphine or morpholine tail as the subcellular targeting group. These fluorescent probes displayed excellent properties in live cell and brain tissue imaging. [ABSTRACT FROM AUTHOR]

In this study, seven new 3(2H)-pyridazinone derivatives expected to show cytotoxic activity in liver and colon cancer cell lines were synthesized. Their structures were confirmed by the IR, 1H-NMR, 13C-NMR spectra and elementary analyses. Compunds V1-V7 were tested on HEP3B (liver cancer) and HTC116 (colon cancer) cell lines for cytotoxicity by using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium] proliferation assay. Human fibroblast cells were used as safety control in these tests. 6-[4-(2-Fluorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-acetyl-2-(2-chlorobenzal)hydrazone (compound V3 ) was the most active agent with respect to HEP3B and HTC116 cell lines. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the solubility of pyridazinone derivative 6-phenyl-4,5-dihydropyridazin-3(2H)-one (PDP-6) in different "polyethylene glycol 400 (PEG 400)+water" mixtures at temperatures "T=293.2 K to 313.2 K" and pressure "p=0.1 MPa". The solubilities of PDP-6 were determined using an isothermal method and correlated with Apelblat, van't Hoff and Yalkowsky–Roseman models. The maximum solubilities of PDP-6 in mole fraction were obtained in neat PEG 400 (8.46×10−2 at T=313.2 K). However, the minimum one was recorded in neat water (7.50×10−7 at T=293.2 K). Apparent thermodynamic analysis showed an endothermic dissolution of PDP-6 in all (PEG 400 water) mixtures. Based on the solubility data of the current study, PDP-6 has been considered as practically insoluble in water and soluble in PEG 400. [ABSTRACT FROM AUTHOR]

The chemoselective reactions of 2‐(5‐mercapto‐4‐phenyl‐4H‐[1,2,4]triazol‐3‐ylmethyl)‐6‐p‐tolyl‐4,5‐dihydro‐2H‐pyridazin‐3‐one (3) with different electrophiles were evaluated. Triazole 3 reacted with alkyl halides in the presence of triethylamine in alcohol to give the corresponding S‐substituted derivatives. On the basis of S‐chemoselective reactions of triazole 3, a series of amino acid 10a–d and dipeptide derivatives 12a–d were prepared via azide coupling of the corresponding hydrazides 9 and 15 with amino acid ester hydrochlorides, respectively. N‐Substituted triazoles 6a–c or 7a–d attached to pyridazin‐3‐one moiety were successfully formed by the reaction of 3 with activated acrylic acid derivatives or with amines. Antibacterial activities of the synthesized derivatives were investigated through correlation with Escherichia coli FabH inhibitory activities using molecular modeling docking software. The antimicrobial activity of synthesized compounds was evaluated, showing best inhibition zone for N‐substituted carboxylic acid 5a and N‐substituted nitrile 5c parallel to the molecular modeling studies. [ABSTRACT FROM AUTHOR]

The Cu(II) complex compound (Cu(C 11 H 17 N 3 O 3 ) 2 Cl 2 (H 2 O) 2 ) was synthesized from reaction between the copper(II) chloride dihydrate and the 4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone. The Cu(II) complex compound in octahedral geometry was characterized using elementel analysis, FT-IR and UV–Vis. spectroscopic techniques. The molar conductance and magnetic susceptibility of the Cu(II) complex were experimentally investigated to confirm octahedral geometry. The quantum chemical computations for molecular geometric parameters, vibrational wavenumber, UV–Vis. parameters, HOMO-LUMO investigations and NBO analysis of the complex compound were performed by using UHSEh1PBE functional in DFT method at the LanL2DZ basis set. The vibrational analysis was performed to determine metal-ligand bond and ligand vibrations. The HOMO and LUMO analyses were investigated to understand charge transfers and electronic transitions in the complex. The electronic configuration, natural charge and coordination environment of the Cu(II) metal ion was investigated via NBO analysis. The experimental results were compared with computed data. [ABSTRACT FROM AUTHOR]

The reaction of 17-ketosteroids and glyoxylic acid followed by treatment with hydrazine affords steroid compounds condensed in the 16 and 17 positions with the pyridazin-3(2H)- one ring. [ABSTRACT FROM AUTHOR]

A novel quinolinyl pyrrolone and quinolinyl pyridazinone derivatives has been synthesized and characterized using different spectroscopic and elemental analysis techniques. Most of the target compounds displayed promising antiproliferative activity; In general, the pyrrolone derivatives 4a-f exhibited higher antiproliferative activity than their corresponding pyridazinone. The pyrrolone 4f showed outstanding antiproliferative activity with moderate selectivity against CNS and renal cancer with selectivity ratio of 3.49 and 3.56, respectively. Compound 4e and 5d experienced tubulin polymerization inhibitory activity comparable to that of vincristine while 4c , 4e and 4d showed good BRAF kinase inhibition compared to Erlotinib. Docking of compound 4e into colchicine binding site and biological assay results revealed that these compounds act mainly through tubulin polymerization inhibitory mechanism and can exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase. [ABSTRACT FROM AUTHOR]

New series of thiazolo[4,5- d ]pyridazin and imidazo[2′,1′:2,3]thiazolo[4,5- d ]pyridazin analogues were designed, synthesized and evaluated for their in vitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC 50 0.05 and 0.06 μM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC 50 0.32 and 0.46 μM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N 1 -nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5- d ]pyridazine ( 18 , 19 ) or imidazo[2,1- b ]thiazoles ( 23 – 25 ) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2′,1′:2,3]-thiazolo[4,5- d ]pyridazine ( 43 – 54 ) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR 1a , mGLuR 5 or mGluR 8. Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR 5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR 2 and mGluR 4 are distinct: the compounds which select for mGluR 2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA A, nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn’s mGluR 1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis. [ABSTRACT FROM AUTHOR]

In this work, the 4-ethoxy-2-methyl-5-(4-morpholinyl)-3(2H)-pyridazinone (or emarfazone, C11H17N3O3) compound, which has many biological functions, has been investigated using FT-IR, 1H and 13C NMR (in CDCl3 solvent), and UV-vis (in ethanol solvent) spectroscopic techniques. Furthermore, the optimized molecular structure, conformational analysis, vibrational frequencies and their assignments, 1H and 13C NMR chemical shift values (in gas phase and CHCl3 solvent), HOMO–LUMO, MEP (molecular electrostatic potential), NBO (natural bond orbital) analyses, and nonlinear optical (NLO) parameters of the title compound in the ground state have been explored by using DFT/HSEH1PBE method with the 6-311++G(d,p) basis set. The electronic absorption maximum wavelengths and oscillator strengths (in gas phase and ethanol solvent) were also obtained at TD-DFT/HSEH1PBE level. A comparison among the experimental and calculated results at the mentioned level indicates that the vibrational frequencies and maximum electronic absorption wavelengths are in good agreement with each other. [ABSTRACT FROM AUTHOR]

Reactions of 5-substituted 3-(arylmethylidene)furan-2(3H)-ones with hydrazine hydrate, hydroxylamine, and guanidine involved opening of the furanone ring. Their hydrazinolysis under mild conditions afforded acyclic 4-oxoalkanoic acid hydrazides which underwent heterocyclization to substituted pyridazinones in boiling ethanol. The presence of an alkyl substituent in the 5-position of the initial furanone favored heterocyclization with the formation of pyrazolidinone derivatives. The reactions of 3-(arylmethylidene)furan-2(3H)-ones with hydroxylamine and guanidine also produced new six-membered heterocycles, 2H-1,2-oxazin-3(4H)-ones and 4,6-disubstituted 3,4-dihydrofuro[2,3-d]pyrimidin-2-amines, respectively. [ABSTRACT FROM AUTHOR]

The reaction of 3‐oxo‐2‐arylhydrazonopropanals with ethyl cyanoacetate in acetic acid containing ammonium acetate was found to afford only 2‐amino‐5‐phenylazonicotinate 9 and not 2‐hydroxy‐6‐substituted‐5‐arylazonicotinates 6, as has been demonstrated by the obtained X‐ray data. Also, we found that the reaction 3‐oxo‐2‐arylhydrazonopropanals with ethyl cyanoacetate in ethanol containing triethylamine affords only the pyridazinone 11 and the obtained X‐ray data for this compound conclusively prove this structure. [ABSTRACT FROM AUTHOR]

Abstract: An efficient N‐arylation of pyridazinones with diaryliodonium salts has been developed without using base or metal catalysts. The reaction tolerated a variety of both diaryliodonium salts and pyridazinone derivatives with diverse functional groups. Furthermore, a drug candidate for treatment of neuropathic pain was synthesized with this procedure in good yield. [ABSTRACT FROM AUTHOR]

Abstract: A series of first-, second-, and third-generation dendronic triazolo-pyridazinones were synthesized in good yields via the CuI-catalyzed azide-alkyne cycloaddition reactions of 4,6-diphenyl-2-(prop-2-yn-1-yl)pyridazin-3(2H)-one, possessing a terminal alkyne functional group with aromatic mono- and diazides with long alkyl and chiral glycol side-chain substituents. The chemical structures of the new compounds were characterized using different spectroscopic methods. The morphology of the dendrons was examined using the scanning electron microscope (SEM) analysis, which revealed the formation of highly ordered nanofiber and nanorod aggregations, directed by π-stacking interactions and van der Waals forces.Graphical abstract: [ABSTRACT FROM AUTHOR]

Inspired by an urgent unmet medical need for development of potent and broad-spectrum antibiotics, we apply herein diverse strategies to obtain novel pyridazinone-vanillyl conjugates having a N(2)-arm of arylpropanamides ( 8a – c ) or vanillyl ionic liquids (Val-ILs) ( 9a – d ) motifs. These new pyridazinone-based antibiotic candidates display remarkable and broad-spectrum antimicrobial efficacy. Combined analysis of pharmacological results coupled with the in Silico derived parameters demonstrated the importance of the chemical nature of the arm in tuning the antimicrobial potency for the target compounds. For instance, 9b (with Val-IL arm) (MIC/MBC = 1.98/2.18 μg/mL) is about 7-fold more potent than 8a (with neutral arm) (MIC/MBC = 13.50/14.12 μg/mL) as Anti- P . aeruginosa agent. The molecular docking study revealed that compound 8a was found to the most effective in binding to the active site of E . coli FabH (PDB code 1HNJ ) with H-bonding, π-stacking and hydrophobic groove interactions having minimum binding energy ΔG b = −14.00 kcal/mol. [ABSTRACT FROM AUTHOR]

With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3- d ]pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1 – 11 were evaluated for their binding at hA 1 , hA 2A and hA 3 ARs and efficacy at hA 2B subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2-yl)thieno[2,3- d ]pyridazin-4(5H)-one) emerged as the best of this series. The simplicity of the synthetic process, the capability of the scaffold to be easily decorated, together with the predicted ADME properties confirm the role of these compounds as promising hits. A molecular docking investigation at the hA 1 AR crystal structure was performed to rationalize the SARs of the herein reported thienopyridazinones. [ABSTRACT FROM AUTHOR]

Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability. [ABSTRACT FROM AUTHOR]

A series of new hybrid benzothiazole containing pyridazinones derivatives were designed and synthesized fulfilling all the pharmacophoric requirements essential for the anticonvulsant activity. In-silico and in vitro studies revealed that some of these hybrid derivatives demonstrated admirable GABA AT inhibitory activity. An attempt has also been made to validate the results of in vitro GABA AT inhibition of the most potent compound SPS-5F (IC 50 9.10 μM) through in vivo anticonvulsant screening. Compound SPS-5F administration significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme. [ABSTRACT FROM AUTHOR]

The stabilization of β-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable β-hairpin folds based on peptide strand N -amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between α-hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N -amino peptide building blocks were then evaluated for their effect on β-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong β-sheet stabilizing effect of the peptide N -amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on β-sheet folding. [ABSTRACT FROM AUTHOR]

Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells. [ABSTRACT FROM AUTHOR]

Through cell-based screening models, we have identified a new compound IMB5043, a thiophenylated pyridazinone, which exerted cytotoxicity against cancer cells. In the present study, we evaluated its antitumor efficacy and the possible mechanism. By MTT assay, IMB5043 inhibited the proliferation of various human cancer cells lines, especially hepatocarcinoma SMMC-7721 cells. IMB5043 blocked cell cycle with G2/M arrest, induced cell apoptosis, and inhibited the migration and invasion of SMMC-7721 cells. As verified by comet assay and γ-H2AX foci formation, IMB5043 caused DNA damage and activated ATM, Chk2 and p53 through phosphorylation. As shown by Gene microarray analysis, the differentially expressed genes in SMMC-7721 cells treated with IMB5043 were highly related to cell death and apoptosis. IMB5043 suppressed the growth of hepatocarcinoma SMMC-7721 xenograft in athymic mice. By histopathological examination, no lesions were found in bone marrow and various organs of the treated mice. Our findings reveal that IMB5043 as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway. IMB5043 may serve as a promising leading compound for the development of antitumor drugs. [ABSTRACT FROM AUTHOR]

Two new pyridazinium-based ionic liquids namely 1-(6-ethoxy-6-oxohexyl)pyridazin-1-ium bromide (S 1 ) and 1-(2-bromoacetyl) pyridazinium bromide (S 2 ) were synthesized and their inhibitive performance towards the corrosion of mild steel in 1 M hydrochloric acid was studied using electrochemical impedance spectroscopy (EIS) at various temperatures (303–333 K). It was shown that the inhibition efficiency increased with the concentration of S 1 and S 2 and reached 84% for S 1 and 82% for S 2 at 10 − 3 M (303 K). Impedance measurements revealed that the charge transfer resistance ( R ct ) increased and the double layer capacitance ( C dl ) decreased with an increase in the concentration of both the inhibitors. The thermodynamic parameters provided the evidence of the inhibitory effect. Langmuir isotherm model fitted well with the adsorption of the studied compounds. Furthermore, spontaneity of the adsorption process, evaluated from the sign of free energy (Δ G ads o ) values, showed an increase upon increase in temperature in the presence of inhibitors. Dynamics simulation indicated the possibility of gradual substitution of water molecules from the iron surface. [ABSTRACT FROM AUTHOR]

A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB 1 and CB 2 receptors. The N -bornyl- S -(5,6-di- p -tolylpyridazin-3-yl)-sulfenamide, compound 11 , displayed good affinity and high selectivity for CB 1 receptors ( K i values of 44.6 nM for CB 1 receptors and >40 μM for CB 2 receptors, respectively). The N- isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB 1 receptors with K i values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB 1 receptor in the [ 35 S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD 50 . However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB 1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist. [ABSTRACT FROM AUTHOR]

Four series of N -methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC 50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds ( 35 , 39 and 43 ) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC 50 values of 0.58 ± 0.15 µM, 0.47 ± 0.06 µM and 0.74 ± 0.12 µM, which were 3.73–5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC 50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out. [ABSTRACT FROM AUTHOR]

In the review, data on the reactions of arylmethylidene derivatives of 3H-furan-2-ones with C-, N-, N,N-, and N,O-nucleophilic agents and amines of the heterocyclic series are systematized. It is demonstrated that the direction of the reaction depends on the structure of initial reagents, the strength of nucleophilic agent, and the reaction conditions. A wide range of acyclic, cyclic, and heterocyclic compounds are obtained: amides, 4-oxoalkanoic hydrazides, pyrrolones, benzofurans, furopyridines, phenanthrenes, pyrosolinones, pyridazinones, oxazines, thiadiazoles, triazolediazepinones, etc. [ABSTRACT FROM AUTHOR]

Some pyridazinones with ortho hydroxy hydrazone were investigated using DFT/B3LYP 6-311 G(d,p) method. Optimized molecules were taken account for NBO analysis by using DFT/B3LYP 6-311+G(d,p) method and information gained NBO analysis gave some important point for predicton of polarization of atoms. Furthermore, electrostaticpotential surfaces (MEP) were calculated and visualized in order to predict charge distribution as well as the shape/volume of the surface of the pyridazinones. HOMO-LUMO orbitals were computed and with these information hardness, electronegativity and global electronegativity index were calculated. For aromaticity of pyridazinone ring HOMA, BIRD and NICS indexes were calculated and aromaticity indexes revealed that which heterocyclic ring was the most aromatic and stable against metabolization effect of enzymes. Electron density map with projection for 2 was plotted and its localization of electron density was discussed. Lipinski's rule of five was calculated for investigated molecules for prediction of oral uptake and drug candidates. [ABSTRACT FROM AUTHOR]

PDE3s belong to the phosphodiesterases family, where the PDE3A isoform is the major subtype in platelets involved in the cAMP regulation pathway of platelet aggregation. PDE3A inhibitors have been designed as potential antiplatelet agents. In this work, a homology model of PDE3A was developed and used to obtain the binding modes of bicyclic heteroaromatic pyridazinones and pyrazolones. Most of the studied compounds adopted similar orientations within the PDE3A active site, establishing hydrogen bonds with catalytic amino acids. Besides, the structure-activity relationship of the studied inhibitors was described by using a field-based 3D-QSAR method. Different structure alignment strategies were employed, including template-based and docking-based alignments. Adequate correlation models were obtained according to internal and external validations. In general, QSAR models revealed that steric and hydrophobic fields describe the different inhibitory activities of the compounds, where the hydrogen bond donor and acceptor fields have minor contributions. It should be stressed that structural elements of PDE3A inhibitors are reported here, through descriptions of their binding interactions and their differential affinities. In this sense, the present results could be useful in the future design of more specific and potent PDE3A inhibitors that may be used for the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Efficient synthesis of phenanthridin-6(5H)-one derivatives 12a-n in a four-component reaction of aldehyde hydrazone, aromatic aldehydes and malononitrile in Q-Tubes is reported. The results showed that the methodology has the advantage of being a one-pot synthesis of tricyclic systems in good yields. Potential routes leading to formation of compounds 12 are discussed. The structures of the synthesized compounds could be unequivocally established via X-ray crystal structure determination and spectroscopic methods. [ABSTRACT FROM AUTHOR]

Nitrogen compounds are widely investigated due to their pharmacological properties such as antihypertensive, antinociceptive, antibacterial, antifungal, analgesic, anticancer and inhibition activities and lately even as pesticide. In this context, we present the synthesis of new compounds: (E)-6-(3,4-dimethoxyphenyl)-3-(3-(3,4-dimethoxyphenyl)acryloyl)-1-(4- R -phenyl)- 5,6-dihydropyridazin-4(1H)-one (with R = H( 1 ), -Cl( 2 ), -Br( 3 ), I( 4 ) and COOH( 5 )) that was carried out by reaction of (1E, 6E)-1,7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione with a substituted phenylamine with general formula p - R -C 6 H 4 NH 2 (R = H ( 1 ), Cl ( 2 ), -Br( 3 ), I( 4 ) and COOH( 5 )). This is the first synthesis report of a pyridazinone using as precursors a curcuminoid derivative and a diazonium salt formed in situ . All compounds were characterized by EA, FT-IR, UV–Vis, Emission, 1 H- and 13 C-NMR spectroscopy and the crystalline and molecular structure of 4 was solved by X-rays diffraction method. DFT and TD-DFT quantum chemical calculations were also employed to characterize the compounds and provide a rational explanation to the spectroscopic properties. To assess the biological activity of the systems, we focused on pesticide tests on compound 2 , which showed an inhibitory effect in plant growth of Agrostis tenuis Higland. [ABSTRACT FROM AUTHOR]

Employing an optimized Pd-catalyzed cross-coupling reaction promoted by CuI, novel N -ferrocenylpyridazinones along with N -phenyl- and N -(2-pyridyl) analogues were synthesized from readily available heterocyclic precursors, iodoferrocene, iodobenzene and 2-bromopyridine. With exception of the ferrocenylation of 6-ferrocenylpyridazin-3(2 H )-one yielding both N - and O-substituted products, the studied reactions exclusively afforded N -aryl lactams. The novel compounds exhibited cytotoxicity towards HEPG2 and HT-29 human malignant cells under in vitro conditions. The measured IC 50 values supplemented with the results of cyclic voltammetry and DFT calculations suggest that the cytotoxic activity of the N - and O -ferrocenyl-substituted derivatives and the decreased effect of the N -phenyl analogues seem to be at least partly associated with the potential to generate reactive oxygen species (ROS). This interpretation, allowing the prediction of characteristic substituent-dependent SAR, was supported by the results of related studies on the practically inactive N -(2-pyridyl)pyridazinones assumed to be present in protonated chelate forms with highly a decreased propensity to undergo ionization. [ABSTRACT FROM AUTHOR]

[Display omitted] • The three-component starting materials are available aldehydes, arylhydrazines and 3-acryloyloxazolidin-2-one. • This strategy exhibits high tolerance towards many functional aldehydes. • The useful tetrahydropyridazines could be achieved in excellent yields by one-step reduction. The three-component synthesis of pyridazinones from aldehydes, arylhydrazines and 3-acryloyloxazolidin-2-one catalyzed by Cu(OTf) 2 has been developed. This strategy exhibits high tolerance towards many functional groups including various aliphatic, aromatic and hetero-aromatic aldehydes to give 2,6-diaryl-4,5-dihydropyridazin-3(2 H)-one products in moderate to high yields. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a leading cause of hospital-acquired infections in the USA and is a major health concern as methicillin-resistant S. aureus and other antibiotic-resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches. Here we have used NMR spectroscopy to determine the molecular basis through which pyridazinone-based small molecules inhibit SrtA. These inhibitors covalently modify the active cysteine thiol and partially mimic the natural substrate of SrtA by inducing the closure of an active site loop. Computational and synthetic chemistry methods led to second-generation analogues that are ~70-fold more potent than the lead molecule. These optimized molecules exhibit broad-spectrum activity against other types of class A sortases, have reduced cytotoxicity, and impair SrtA-mediated protein display on S. aureus cell surface. Our work shows that pyridazinone analogues are attractive candidates for further development into anti-infective agents, and highlights the utility of employing NMR spectroscopy and solubility-optimized small molecules in structure-based drug discovery. [ABSTRACT FROM AUTHOR]

Herein, we report photophysical properties of a novel and biologically active 3( 2H)-pyridazinone derivative 5-(4-chloro-2-hydoxy-phenyl)-2-phenyl- 2H-pyridazin-3-one [CHP] molecule using solvatochromic approaches. Absorption and fluorescence spectra of CHP molecule have been measured at room temperature in various solvents of different polarities. From this, it is observed that the positions, intensities and shapes of the absorption and emission bands are usually modified. Experimentally, the ground and excited state dipole moments are estimated using solvatochromic shift method which involves Lippert's, Bakshiev's and Kawski-Chamma-Viallet's equations. Theoretically, the ground state dipole moment was estimated using the Gaussian-09 program. The value of ground state dipole moment estimated using experimental and theoretical methods are well correlated. This inference that the molecular geometry is taken for CHP molecule under theoretical and experimental methods are similar. Further, we observed that the excited state dipole moment ( μ ) is greater than the ground state dipole moment ( μ ) which indicates that the excited state is more polar than the ground state. Furthermore, we have estimated an angle between the ground and excited state dipole moments. In addition, we have estimated the fluorescence quantum yield of CHP molecule using Rhodamine B as a standard reference in different solvents. [ABSTRACT FROM AUTHOR]

Herein, we have studied the analysis of fluorescence quenching for newly synthesized biologically active 3( 2H)-pyridazinone derivative 5-(5-bromo-2-hydroxy-phenyl)-2-phenyl- 2H-pyridazin-3-one [BHP] by various concentrations of aniline using UV-Visible spectroscopy, fluorescence spectroscopy and time-correlated single photon counting technique in five different solvents namely, methanol, ethanol, propan-2-ol, dimethylsulfoxide and ethyl acetate at room temperature. The fluorescence intensity of BHP molecule decrease with increasing in the aniline concentration and it is studied using the Stern-Volmer relation. The obtained Stern-Volmer plots were found to be linear in all the five solvents. The various parameters responsible for the fluorescence quenching such as quenching rate parameters ( k ), diffusion rate parameter ( k ) and the probability of quenching per encounter ( p) were experimentally calculated in all five solvents. An activation energy of quenching ( E ) was calculated using the values of activation energy of diffusion ( E ) and p. It was found that the values of E are greater than E in all five solvents studied. Further, it is inferred that the fluorescence quenching reactions in BHP molecule are more significantly affected by activation energy processes. [ABSTRACT FROM AUTHOR]

Recently we developed [18F] 4-(2-fluoroethoxy)- 2H-chromen-2-one as a novel 18F myocardial perfusion imaging radiotracer. It was synthesized in good radiochemical yield (>90%). The total time from radiosynthesis to its purification was less than 40 min, with excellent radiochemical purity (≥99%). It showed good stability over a period of 5 h at room temperature. The partition coefficient (log P) of radiotracer was found to be 2.70, suggesting the lipophilic nature of radiotracer. Ex vivo biodistribution study of radiotracer in normal Wistar rats for 30 min postinjection, demonstrated a good heart uptake (>1.3% ID/g) and favorable pharmacokinetics. Additionally, the radiotracer showed significant excretion (>11% ID) by liver, which is indicative of its rapid clearance. Further, in vivo biodistribution study of radiotracer in New Zealand White rabbit provided the clear PET/CT images of cardiomyocytes and myocardial perfusion. All these experimental findings suggest that [18F] 4-(2-fluoroethoxy)-2H-chromen- 2-one could be used as a potential hit for myocardial perfusion imaging. [ABSTRACT FROM AUTHOR]

Pyridazinone derivatives have been investigated either pre-clinically or clinically in the treatment of various cardiovascular diseases. The main problems associated with these drugs are the poor aqueous solubility and toxicity. Therefore, in the current study, the solubility of pyridazinone derivative i.e. 6-phenyl-4,5-dihydropyridazin-3(2H)-one [coded as PDP-6] was determined in eleven different neat solvents at temperatures “ T = 293.2 K to 313.2 K” and “atmospheric pressure p = 0.1 MPa”. Experimental mole fraction solubilities of PDP-6 were correlated well with van't Hoff and Apelblat models with mean percent deviation of < 6.0%. The mole fraction solubilities of PDP-6 at “ T = 313.2 K” were recorded highest in dimethyl sulfoxide [DMSO] (6.77 × 10 − 1 ) followed by 2-(2-ethoxyethoxy) ethanol (Transcutol®) (5.24 × 10 − 1 ), polyethylene glycol-400 [PEG-400] (8.47 × 10 − 2 ), ethyl acetate [EA] (1.45 × 10 − 2 ), ethylene glycol [EG] (1.09 × 10 − 2 ), propylene glycol [PG] (1.03 × 10 − 2 ), 2-butanol (7.78 × 10 − 3 ), 1-butanol (7.68 × 10 − 3 ), ethanol (6.96 × 10 − 3 ), isopropyl alcohol [IPA] (6.51 × 10 − 3 ) and water (1.61 × 10 − 6 ) and similar trend was also recorded at all five different temperatures investigated. “Apparent thermodynamic analysis” on mole fraction solubilities of PDP-6 indicated an endothermic dissolution of PDP-6 in all neat solvents studied. Based on these data, PDP-6 has been proposed as practically insoluble in water, sparingly soluble in ethanol, IPA, EG, PG, EA, 1-butanol and 2-butanol, soluble in PEG-400 and very soluble in DMSO and Transcutol®. [ABSTRACT FROM AUTHOR]

A novel photocatalytic hydrazonyl radical-mediated radical cyclization/allylation cascade reaction of β,γ-unsaturated hydrazones is developed using allyl sulfones and Morita-Baylis-Hillman adduct as allyl sources, which provides an efficient and practical access to various diversely functionalized dihydropyrazoles and tetrahydropyridazines. The reaction is enabled by controllable generation of hydrazonyl radicals via an oxidative deprotonation electron transfer strategy and selective trapping of the resultant C-centered radicals under visible light irradiation. [ABSTRACT FROM AUTHOR]

A class of pyridazinone derivatives as near-infrared optical probes in fluorescence microscopy images was designed. The design strategy consisted of the stepwise extension and modification of pyridazinone by expansion of the electron-donating moiety to a larger π-conjugated system and anchoring a subcellular directing group such as triphenylphosphine or morpholine. All the desired products were successfully applied in cell imaging with high subcellular colocalization. Furthermore, these fluorescent probes showed excellent performance in mouse-brain imaging. [ABSTRACT FROM AUTHOR]

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model. [ABSTRACT FROM AUTHOR]

A selective phosphoramidation and phosphonation of benzoxazole was developed with trialkyl phosphites in the presence of iodine under mild conditions. In the reaction, the transformation completes in 10 min at room temperature and the substrates are well tolerant, as 2-substituted azoles could afford the quaternary carbon-centered products. Significantly, phosphites could be selectively introduced into the C- and N-positions of the benzoxazoles by controlling the addition sequence and the ratio of substrates. [ABSTRACT FROM AUTHOR]

The rhodium-catalyzed addition of pyridazinones to terminal allenes furnished the corresponding branched N2-allylated products in good yields with high regio- and enantioselectivities. A broad functional group compatibility was observed, and assorted synthetic transformations of the N-allylpyridazinones led to the preparation of a small library of N2-functionalized pyridazinones. Labeling experiments with deuterated substrates provided insights into the underlying reaction mechanism. [ABSTRACT FROM AUTHOR]

Herein, we report the spectroscopic interactions of titanium dioxide (TiO 2 ) nanoparticles (NPs) with pharmacologically active 3( 2H )-pyridazinone derivative, viz., 5-(2-Hydroxy-4-methyl-phenyl)-2-phenyl-2H-pyridazin-3-one [HMP] in an ethanol solvent using UV–Visible spectrophotometer, fluorescence spectrophotometer and time-correlated single photon counting technique at room temperature. The observed values of absorption, fluorescence intensity and fluorescence lifetime of HMP molecule decrease with increasing in the TiO 2 NPs concentration. From the linear Stern-Volmer (S-V) plot in steady state and transient state which indicates the presence of dynamic quenching. The association constant ( k a ) and quenching constant ( K SV ) have been estimated using Benesi–Hildebrand and S-V equations respectively. Further, from the fluorescence data we calculated the binding constant and number of binding sites, the results reveals that there exists one binding site in HMP molecule for TiO 2 NPs. In addition, we studied the energy transfer in fluorescence quenching by Forster's non-radiative energy transfer (FRET) theory. Results, signified that the fluorescence quenching of the HMP molecule is due to the energy transfer from HMP molecule to TiO 2 NPs. The present investigation may be adopted in solar energy materials and also exploited in a variety of applications such as biological sensing, medical diagnosis etc. [ABSTRACT FROM AUTHOR]

The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras-PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity. We delineate the structure-property relationship and in vivo pharmacokinetic (PK) and toxicokinetic (Tox) studies for pyrazolopyridazinone-based K-Ras-PDEδ inhibitors. These findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic Ras. [ABSTRACT FROM AUTHOR]