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Transient receptor potential canonical 5 (TRPC5) is a calcium-permeable non-selective cation channel involved in various pathophysiological processes, including renal injury. Recently, GFB-887, an investigational pyridazinone TRPC5 inhibitor, demonstrated significant therapeutic potential in a Phase II clinical trial for focal segmental glomerulosclerosis (FSGS), a rare and severe form of chronic kidney disease (CKD). In the current study, based on the structure of GFB-887, we conducted extensive structural modification to explore novel TRPC5 inhibitors with desirable drug-like properties and robust nephroprotective efficacy. A series of pyridazinone derivatives featuring a novel tetrahydroimidazo[1,2- a ]pyrazine scaffold were synthesized and their activities were evaluated in HEK-293 cells stably expressing TRPC5 using a fluorescence-based Ca2+ mobilization assay. Among these compounds, compound 12 is turned out to be a potent TRPC5 inhibitor with apparent affinity comparable to the parent compound GBF-887. Compound 12 is highly selective on TRPC4/5 over TRPC3/6/7 and hERG channels, along with acceptable pharmacokinetic properties and a favorable safety profile. More importantly, in a rat model of hypertension-induced renal injury, oral administration of compound 12 (10 mg/kg, BID) efficaciously reduced mean blood pressure, inhibited proteinuria, and protected podocyte damage. These findings further confirmed the potential of TRPC5 inhibitors on the CKD treatment and provided compound 12 to be a valuable tool for exploring TRPC4/5 pathophysiology. [Display omitted] • Pyridazinone derivatives featuring tetrahydroimidazo[1,2- a ]pyrazine scaffold were synthesized as potent TRPC5 inhibitors. • Compound 12 selectively inhibited TRPC4/5 over TRPC3/6/7 and hERG channels. • Compound 12 displayed acceptable pharmacokinetic properties. • Compound 12 suppressed hypertension-induced proteinuria and podocyte injury in DOCA-salt rats. [ABSTRACT FROM AUTHOR]

• Under the impact of ultrasonic irradiation in HFIP: THF solvent, pyridazinone, triazinone, and phthalimide-containing epoxides, CS 2 , and various primary/secondary amines reacted to synthesize the biologically important 2‑hydroxy dithiocarbamates in the current work. • DFT simulations are utilized in the computational study to optimize the structure and determine the interaction energies and HOMO-LUMO energy gap. • The hirshfeld surface analysis was used to evaluate the intermolecular interactions of compounds 4a and 4p within their crystal lattices. • Compounds 4a-4t docking experiments revealed that compounds 4a, 4e , and 4o may operate as potent anti-inflammatory drugs by inhibiting the cyclooxygenase-2 enzyme. • A molecular dynamic simulation study was also conducted for 100 ns to assess the stability of the most effective compound 4o. Under the influence of ultrasonic irradiation, pyridazinone, triazinone, or phthalimide containing 2‑hydroxy dithiocarbamates, a biologically relevant novel organo-sulfur compound, was synthesized. Detailed characterization, computational, and molecular docking studies are being investigated. Molecular interactions were studied using 3D Hirshfeld surfaces and corresponding 2D fingerprint plots. Theoretical (DFT) studies on the molecular structure, HOMO, LUMO, and quantum chemical descriptors were performed at the B3LYP/6–311++ G (d,p) level of theory. At the same time, the interaction energy was computed using the B3LYP/6–31G(d,p) level of theory. The FMO study revealed that molecules 4a and 4p in the gas phase have 3.545 eV and 3.263 eV HOMO-LUMO energy gaps, respectively, and they are hence kinetically stable. Quantum chemical calculations confirm the electrophilic character of compounds 4a and 4p , as the molecule is stable and highly electrophilic. The interactions of 2‑hydroxy dithiocarbamate derivatives (4a-4t) with the ligand-binding site of the target COX-2 (cyclooxygenase-2) enzyme were investigated using in-silico molecular docking experiments. Compared to the standard medicine celecoxib, the results showed that most synthesized derivatives had better glide scores and interaction. The docking study of all the synthesized compounds revealed that compounds 4a, 4e , and 4o interact well with the COX-2 enzyme as anti-inflammatory drugs. Molecular dynamic simulation was utilized to validate the docking study and explore the stable binding site and interaction of compound 4o , which is the most potent. The findings indicated that compound 4o exhibited better stability and interaction when compared to the reference drug. The ultrasound-assisted HFIP-induced synthesis of novel pyridazinone, triazinone, and phthalimide-containing biologically relevant synthesis of 2‑hydroxy dithiocarbamates, as well as their crystal structure, computational characteristics, and molecular docking study, is reported here. The docking investigation of all synthesized compounds demonstrated that compounds 4a, 4e , and 4o interact well with the COX-2 enzyme as anti-inflammatory drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Employing pre-existing functionalized scaffolds to generate focused libraries exemplifies an expedited approach in terms of synthetic feasibility and efficiency. This strategic synthesis is particularly well-suited for scaffolds that are unattainable with DNA-compatible chemical tools. This manuscript utilizes pyridazinone as a paradigmatic scaffold to elucidate the synthetic workflow. Three functionalized pyridazinone reagents were obtained by conventional organic chemistries and then applied to prepare corresponding DNA-encoded libraries (DELs) by robust DNA-compatible reactions and abundant building blocks (BBs), ensuring both diversity and quality in the final libraries. The feasibility of these focused DELs were confirmed by subsequent affinity selection and off-DNA validation against the BRD4 target. [ABSTRACT FROM AUTHOR]

• Flame-retardant effect of pyridazinone on bio-based epoxy resin was detected. • Strong yet tough N-rich hollow vesicles were formed via "radical capturing" effect. • Potential for high value-added conversion from resin carbon to functional carbon. Aromatic nitrogen heterocyclic structure is a key building block of high-performance polymer materials and nitrogen-doped porous carbons, yet systematic studies on its flame-retardant effects and carbonization mechanisms in thermoset materials is still lacking. Here, a pyridazinone embedded bio-based epoxy resin (CSPZ-EP) cured by 4,4ʹ-methylenedianiline (DDM) was prepared. Benefiting from the rigid biphenyl-like pyridazinone structure and the high cross-linking density originated from the self-catalyzed transesterification, the cured CSPZ-EP/DDM can easily pass the UL-94 test with a V-0 rating suggesting excellent intrinsic flame retardancy. The cone calorimeter results further demonstrated that the peak heat release rate, the total heat release and flame growth rate of CSPZ-EP/DDM were significantly reduced by 84.4 %, 28.4 % and 90.5 %, respectively, compared with those of bisphenol A epoxy resin. The higher graphitization degree of the char residues and a large amount of non-flammable pyrolysis gas ejection synergistically prevented the further spread of fire. Strong yet tough nitrogen-rich char layer formed after thermal ablation together with the renewable features and the facile preparation route of CSPZ-EP/DDM make it a potential precursor for heteroatom porous carbons. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4- d ]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model. A series of pyrazolo[3,4- d ]pyridazinone derivatives were synthesized. Kinase inhibition, cell proliferation, and whole blood stability assays were performed, allowing us to explore structure−activity relationship and to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Compound 10h displayed highly potent antitumor efficacy in the NCI-H1581 xenograft model. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] An expedient access to novel 4-phosphonomethyl-containing 2,6-disubstituted 4,5-dihydropyridazin-3(2 H)-ones involves the reaction of β-phosphono γ'-keto ester intermediates with hydrazines. The construction of the pyridazinone ring allows the installation of various substituents at the positions 2 and 6 as well as a valuable 4-positioned phosphonomethyl fragment. [ABSTRACT FROM AUTHOR]

[Display omitted] The "clip-cycle" synthesis of 2-pyridazinones containing enaminonitriles from thioesters with dicyanohydrazones is achieved through a AgOAc-promoted acylation-cyclization-tautomerization cascade reaction. Moreover, the obtained 2-pyridazinones are further transformed into biologically significant bicyclic-fused pyridazinones exhibiting intriguing fluorescence emission properties. Additionally, quantum chemical calculations were performed to provide a rational explanation for the observed photophysical characteristics. [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]

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]

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]

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]

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]

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]

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]

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]

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]

Disulfide bonds contribute to protein stability, activity, and folding in a variety of proteins, including many involved in bacterial virulence such as toxins, adhesins, flagella, and pili, among others. Therefore, inhibitors of disulfide bond formation enzymes could have profound effects on pathogen virulence. In the Escherichia coli disulfide bond formation pathway, the periplasmic protein DsbA introduces disulfide bonds into substrates, and then the cytoplasmic membrane protein DsbB reoxidizes DsbA's cysteines regenerating its activity. Thus, DsbB generates a protein disulfide bond de novo by transferring electrons to the quinone pool. We previously identified an effective pyridazinone-related inhibitor of DsbB enzymes from several Gram-negative bacteria. To map the protein residues that are important for the interaction with this inhibitor, we randomly mutagenized by error-prone PCR the E. coli dsbB gene and selected dsbB mutants that confer resistance to this drug using two approaches. We characterized in vivo and in vitro some of these mutants that map to two areas in the structure of DsbB, one located between the two first transmembrane segments where the quinone ring binds and the other located in the second periplasmic loop of DsbB, which interacts with DsbA. In addition, we show that a mutant version of a protein involved in lipopolysaccharide assembly, lptD4213, is synthetically lethal with the deletion of dsbB as well as with DsbB inhibitors. This finding suggests that drugs decreasing LptD assembly may be synthetically lethal with inhibitors of the Dsb pathway, potentiating the antibiotic effects. [ABSTRACT FROM AUTHOR]

Here, we first time report the flexible tripodal molecules, contained propylene as a linker, thiocyanuric acid as central core and, p -nitro phenol 1 and pyridazinone 2 as terminal for conformational studies. The conformational studies of these tripodal molecules have been carried by X-ray crystallography, 2D-NOESY spectra and computational studies. Both the molecules have shown folded conformations in solid and solution state however solid state conformation is not stable in gaseous state. [ABSTRACT FROM AUTHOR]

In the last few years, cannabinoid type-2 receptor (CB 2 R) selective ligands have shown a great potential as novel therapeutic drugs in several diseases. With the aim of discovering new selective cannabinoid ligands, a series of pyridazinone-4-carboxamides was designed and synthesized, and the new derivatives tested for their affinity toward the h CB 1 R and h CB 2 R. The 6-(4-chloro-3-methylphenyl)-2-(4-fluorobenzyl)- N -( cis- 4-methylcyclohexyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide ( 9 ) displayed high CB 2 -affinity ( K i CB 2 = 2.0 ± 0.81 nM) and a notable selectivity ( K i CB 1 / K i CB 2 > 2000). In addition, 9 and other active new synthesized entities have demonstrated to behave as CB 2 R inverse agonists in [ 35 S]-GTPγS binding assay. ADME predictions of the newly synthesized CB 2 R ligands suggest a favourable pharmacokinetic profile. Docking studies disclosed the specific pattern of interactions of these derivatives. Our results support that pyridazinone-4-carboxamides represent a new promising scaffold for the development of potent and selective CB 2 R ligands. [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]

A new series of pyrazolo[3,4- d ]pyridazin-7-one derivatives were synthesised and evaluated for their in vitro antileishmanial activity against Leishmania amazonensis promastigote and axenic amastigote forms. The results showed that the pyrazolo[3,4- d ]-pyridazin-7-one- N -acylhydrazone-(bi)thiophene hybrids 5b , 6b and 6d exhibit better antileishmanial activity with IC 50 84.96, 3.63 and 10.79 μM, against the promastigote form and IC 50 32.71, 2.32 and >100 μM against the axenic amastigote form, respectively. The active compounds had their cytotoxicity tested against macrophages and fibroblast cells with a higher selectivity index than 10 for compounds 6b and 6d . Molecular docking studies were performed for all active compounds using the enzyme trypanothione reductase (TR) to investigate a possible action mechanism. The results suggested that active compounds had interactions with the residues of amino acids Gly 13, Thr 51, Thr 160, Gly 161, Tyr 198, Arg 287, Asp 327, Thr 335, which may inhibit the enzyme TR. [ABSTRACT FROM AUTHOR]

In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D 2 , K i = 0.5 ± 0.07 nM; 5-HT 1A , K i = 5.9 ± 0.8 nM; 5-HT 2A , K i = 0.3 ± 0.01 nM; 5-HT 6 , K i = 0.5 ± 0.04 nM) and combined with low affinities for the H 1 , 5-HT 2C , and adrenergic α 1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia. [ABSTRACT FROM AUTHOR]

Pyridazinones have drawn a substantial attention within the field of research analysis and development. The moiety is a subject matter of intensive research because of its wide spectrum of biological activities and therapeutic applications. The synthesis of pyridazinone and investigation of their chemical and biological activities have gained additional importance in recent years. In this review, we have compiled and discussed various biological and therapeutic potential of pyridazinone derivatives. [ABSTRACT FROM AUTHOR]

Heterocycle-fused azepines are discussed as potent 5-HT 2C receptor agonists with excellent selectivity over 5-HT 2B agonism. Synthesis and structure activity relationships are outlined for a series of bicyclic pyridazino[3,4- d ]azepines. By comparison with earlier published work, in vitro assays predict a high probability for achieving CNS penetration for a potent and selective compound 15a , a pre-requisite to achieve in vivo efficacy. [ABSTRACT FROM AUTHOR]

In this study we designed a series of proteasome inhibitors using pyridazinone as initial scaffold, and extended the structure with rational design by computer aided drug design (CADD). Two different synthetic routes were explored and the biological evaluation of the phthalazinone derivatives was investigated. Most importantly, electron positive triphenylphosphine group was first introduced in the structure of proteasome inhibitors and potent inhibition was achieved. As 6c was the most potent inhibitor of proteasome, we examined the structure–activity relationship (SAR) of 6c analogs. [ABSTRACT FROM AUTHOR]

N -Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2 H )-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2 H )-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a , 13a and 27b , which had EC 50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC 50 = 45 nM), while 13a and 27b showed a moderate preference for FPR2 (EC 50 = 35 and 61 nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling. [ABSTRACT FROM AUTHOR]

A facile and general method for the synthesis of pyridazino[6,1- b ]pyrrolo[1,2- a ]quinazolin-9(1 H )-one derivatives via a reaction of 2-aminobenzohydrazide and 1,7-dichloro-heptan-4-one catalyzed by iodine in the presence of excess NaHCO 3 is described. This is a tandem reaction to construct three new rings and a chiral quaternary carbon center in one-pot procedure. Two possible pathways in the formation of the second heterocycle are proposed, and they are confirmed by the key intermediates of pyrrolo[1,2- a ]quinazolin-5(1 H )-ones which are selectively obtained via controlling the ratio of base. [ABSTRACT FROM AUTHOR]

Trypanosomal phosphodiesterases B1 and B2 (TbrPDEB1 and TbrPDEB2) play an important role in the life cycle of Trypanosoma brucei , the causative parasite of human African trypanosomiasis (HAT), also known as African sleeping sickness. Knock down of both enzymes leads to cell cycle arrest and is lethal to the parasite. Recently, we reported the phenylpyridazinone, NPD-001, with low nanomolar IC 50 values on both TbrPDEB1 (IC 50 : 4 nM) and TbrPDEB2 (IC 50 : 3 nM) ( J. Infect. Dis. 2012 , 206 , 229). In this study, we now report on the first structure activity relationships of a series of phenylpyridazinone analogs as TbrPDEB1 inhibitors. A selection of compounds was also shown to be anti-parasitic. Importantly, a good correlation between TbrPDEB1 IC 50 and EC 50 against the whole parasite was observed. Preliminary analysis of the SAR of selected compounds on TbrPDEB1 and human PDEs shows large differences which shows the potential for obtaining parasite selective PDE inhibitors. The results of these studies support the pharmacological validation of the Trypanosome PDEB family as novel therapeutic approach for HAT and provide as well valuable information for the design of potent TbrPDEB1 inhibitors that could be used for the treatment of this disease. [ABSTRACT FROM AUTHOR]

A series of sulfonamide derivatives ( 2a – l ) incorporating substituted pyridazinone moieties were investigated for the inhibition of two human cytosolic carbonic anhydrase isoforms, hCA I and hCA II. All these compounds, together with the clinically used sulfonamide acetazolamide were investigated as inhibitors of the physiologically relevant isozymes I and II. These sulfonamides showed very strong inhibition against all these isoforms with K I ’s in the range of 0.98–8.5 nM which makes such molecules possible to be used as leads for discovery of novel effective CA inhibitors targeting other isoforms with medicinal chemistry applications. [ABSTRACT FROM AUTHOR]

Over activation of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein we describe the design, synthesis and biological activities of novel, ATP-competitive, c-Met tyrosine kinase inhibitors that are members of the 6-aryl-2-(3-(heteroarylamino)benzyl)pyridazinone family. A structure-activity relationship (SAR) study of these substances led to identification of pyridazinone 19 as a highly selective and potent c-Met tyrosine inhibitor, which displays favorable pharmacokinetic properties in mice and significant antitumor activity against a c-Met driven EBC-1 tumor xenograft. [ABSTRACT FROM AUTHOR]

BTK inhibitor GDC-0834 ( 1 ) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23 , possessing improved potency, metabolic stability and preclinical properties. [ABSTRACT FROM AUTHOR]

Six novel photochromic bisarylpyridazinones containing 2,5-dimethylthiophene or 5-methyl-2-phenylthiazole unit were synthesized, and their photochromic and fluorescence properties were investigated. The bisarylpyridazinones underwent reversible color change upon irradiation with UV or visible light. The effect of solvents on the absorption spectra of the bisarylpyridazinones was investigated. The closed-ring forms of bisarylpyridazinones displayed negative solvatochromism which was attributed to the high dipolar characters of the molecule. The open-ring forms of bisarylpyridazinones showed fluorescence at 400–480 nm upon excitation at 302 nm, and the intensities of emission bands gradually decreased during the ring-closing photoreactions. Among the synthesized bisarylpyridazinones, 4,5-bis(5-methyl-2-phenylthiazol-4-yl)-2-methyl(or 2-phenyl) pyridazin-3(2H)-ones ( 5O and 6O ) displayed rather large absorption and emission spectral change, higher quantum efficiency during the photoreaction compared to others. A high conversion ratio (94%) to the closed form was observed for 5O . [ABSTRACT FROM AUTHOR]

• Structure elucidation from single crystal X-ray data has been performed. • TDDFT calculation has been carried out. • Hirshfeld surface analysis has been performed. • Potential energy scanning has been carried out. • Absorption and emmision study of the compound has been performed. The present study unfolds the synthesis and characterization of a new butylidine linked hetero dimer of pyridazinone (PNP). The crystal structure analysis of PNP reveals that it exhibited infinite 1D linear chains connected through C-H∙∙∙O interaction and interlayer connectivity was supported by the unconventional orthogonal dipolar interaction via nitro-aromatic (ONO 2 ···π(C)Ar). These interactions are also described using DFT calculations and are potentially studied. Here we discuss the influence of crystal structure on the photophysical properties of a new solid state emitter containing brick layer packing. Furthermore, we conducted detailed exploration of the intermolecular interactions that maintain the crystal packing of the structure by employing the Hirshfeld surface analysis and its corresponding two-dimensional fingerprint plots revealing that the C-H∙∙∙O interaction mainly stabilized the crystal structure. Time-dependent density functional theory (TDDFT) studies and observed nitro aromatic interactions (ONO 2 ∙∙∙(C)Ar) in the crystal helped to explain the electronic behaviour of PNP. The validity of the computations is supported by a good agreement between the estimated and experimental values of the excitation energy transfer. Furthermore, we conducted detailed research on the Hirshfeld surface analysis and the intermolecular interactions that stabilize the crystal packing using their corresponding two-dimensional fingerprint plot. Some standard thermodynamical parameters such as specific heat, entropy and free energy have also been computed. In addition to this, the variation of specific heat with temperature has been explored. [Display omitted] [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the most common kind of cancers in clinical, and its clinical treatment is quite difficult. The latest research suggests that pyridazinone with a novel molecular skeleton shows excellent activity against hepatocellular carcinoma in vitro and in vivo. Considering YHHU-759 as the leading compound for reasonable structure modification, a series of 3,3′-bipyridazine derivatives including 8 novel compounds in this study were designed, synthesized and screened for their anti -hepatoma activities against liver cancer cell lines SMMC-7721, BEL-7402 and QGY-7703 in vitro. The result shows that all of the 3,3′-bipyridazine derivatives have good anti -hepatoma activities. [ABSTRACT FROM AUTHOR]

A new one-pot method, for the synthesis of polysubstituted pyrrolo[3,4- d ]pyridazinones, is presented. The protocol consists in cascade reactions performed in the same media: (i) the thermal in situ pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds, via the 1,2-addition of 1,3-dicarbonyl compounds to 2 H -azirine intermediates; (ii) the nucleophilic addition of hydrazines to the ketone group present in the pyrroles previously formed, followed by intramolecular cyclization with the bordering ester, which furnishes the respective pyrrolo[3,4- d ]pyridazinones, substituted at the pyrrole and/or pyridazinone rings. All transformations occur in a two-step one-pot methodology, and a series of ten new compounds were obtained at yields of 42–87%. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the analgesic as well as anti-inflammatory activities of the new pyrrolo[3,4-d]pyridazinone derivatives. Moreover, the present study attempted to assess some of the mechanisms involved in the pharmacological activity of these compounds. In the previous studies it was shown that these compounds were highly active in the phenylbenzoquinone-induced ‘writhing syndrome’ test and had much lower activity in the hot plate, which indicates that mainly peripheral mechanisms of analgesia are involved in their effects. In these extended studies the analgesic activity of two tested compounds (4c, 4f) was confirmed in some animal models of pain. The studied compounds showed a significant and dose-related antinociceptive effect in the models of pain induced by formalin, capsaicin and glutamic acid. Both compounds decreased the edema formation and one of them (4c) attenuated mechanical hyperalgesia in carrageenan-induced paw inflammation in rats. Furthermore, both compounds inhibited cell migration, plasma exudation and nociceptive reaction in zymosan A-induced mouse peritonitis. In the subsequent studies, including experiments on isolated organs (ileum, trachea, aorta), radioligand assays and biochemical tests, it was demonstrated that analgesic and anti-inflammatory effects of the investigated structures are largely due to their competitive antagonism for histamine H 1 receptor. The influence on the level of cAMP in inflammatory cells (shown in RAW 264.7 macrophages) and subsequent inhibition of cytokine (TNFα, IL-1β) release can also be one of the important mechanisms of their action. Moreover some additional mechanisms may also be involved in the eventual analgesic effect of tested pyrrolo[3,4-d]pyridazinone derivatives. [ABSTRACT FROM AUTHOR]

A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for their c-Met inhibitory activity in enzyme and cellular assay. An analysis of the SAR results arising from computer modeling analysis of members of the library led to the proposal that in order to obtain optimal inhibitory activity in cellular systems the lipophilic/hydrophilic properties of individual structural fragments in the inhibitors need to match those of corresponding binding pockets in the enzyme. Guided by this proposal, the quinoline-pyridazinone 8a , containing hydrophobic 6-indolyl pyridazinone and quinoline moieties along with a hydrophilic morpholine terminal group, was designed and synthesized. The results of studies with this substance showed that it is a selective c-Met inhibitor with both a high enzyme inhibition IC 50 value of 4.2 nM and a high EBC-1 cell proliferation inhibition IC 50 value of 17 nM. [ABSTRACT FROM AUTHOR]

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 β ( 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 IC 50 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. [ABSTRACT FROM AUTHOR]

In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development. [ABSTRACT FROM AUTHOR]

Condensed polycyclic heteroaromatic cations bearing a bridgehead nitrogen with pyridazino[1′,6′:1,2]pyrido[3,4- b ]indolinium and pyridazino[1,6- a ]benzimidazolium structures were assayed as inhibitors of LPS-induced TNF-α production by THP-1 cells. The hit compound 1e , which had the best IC 50 value (4.49 μM) and low toxicity, was further assayed on human PMBCs (IC 50 3.91 μM) and monocytes (IC 50 1.82 μM). This compound also inhibited TNF-α production following poly I:C stimulation of human monocytes and monocyte-derived dendritic cells; in the latter case, inhibition of IL-12 production was also observed. Compound 1e was also able to inhibit TNF-α expression at the transcriptional level and proved to be effective in vivo . Compound 1e is an interesting potential therapeutic agent in IMIDs. [ABSTRACT FROM AUTHOR]

The molecular structure and relative stabilities of the six possible isomers of 6-hydroxy-3(2H)-pyridazinone (DHP) in the gas phase and in solutions of different polarities are predicted using the B3LYP/6-311++G(d,p) method. The oxo-hydroxo isomer is the most stable form in the gas phase and in solution. These results agree with our reported X-ray structure. The effect of solvents on the spectroscopic properties of the most stable isomer has been studied using the polarized continuum method (PCM) at the same level of theory. The vibrational spectra of the compound studied are calculated and compared with the experimentally measured FTIR spectra. The electronic spectra in gas phase and in solution were calculated using the TD-DFT method. The most intense absorption band is predicted at 312.4 nm and belongs mainly to a π → π * transition. In polar solvents, this spectral band undergoes a hypsochromic shift. Two stable dimer forms were calculated at same level of theory. Dimer A is more stable than dimer B, by 6.66 kcal mol −1 . The former is stabilized by stronger O H⋯O H-bonds compared to the weaker N H⋯O interactions in the latter. The effect of these H-bonding interactions on the molecular structure and vibrational spectra of these compounds are predicted. NBO analyses were carried out to investigate the stabilization energy of various inter- and intramolecular charge transfer interactions within the systems studied. [ABSTRACT FROM AUTHOR]

• Design, synthesis and aldose reductase (ALR2) inhibitory effect of novel pyridazinone derivatives are presented. • 21 new compounds were synthesized and evaluated against ALR2. • All the compounds showed micromolar or submicromolar activity against ALR2 with IC 50 values lower than 1.9 µM. • Compound 3 was docked to 4LB4 with a docking score of -7.962. The inhibitor-active site interactions were observed through Trp 20, Lys 21, and Trp 111. • 2-substituted-6-aryloxo-pyridazinone moiety was found as a suitable scaffold for ALR2 inhibition. The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol and then converted to fructose. The first and rate limiting enzyme of this pathway, aldose reductase (ALR2), is a drug target for treating diabetic complications and inflammation. Given the common features of the known inhibitors, we designed a series of pyridazinone bearing benzoic acid derivatives and then we carried the carboylic acid group onto pyridazinone and synthesized them. We evaluated the compounds against ALR2. Our results showed that all the compounds showed submicromolar or low micromolar inhibitory activity against ALR2. Compound 1 and 3 were found more active than the reference compound (epalrestat) with IC 50 values of 0.278 µM (K i =0.042±0.006 µM, competitive) and 0.188 µM (K i =0.024±0.001 µM, competitive) respectively. Moreover, non carboxylic acid derivative 16c and the ester counterparts of 1, 3, and 12 (1c, 3c, and 12c) showed submicromolar activity against ALR2. According the results, we are able to establish some SARs in order to use in our further studies. [Display omitted] [ABSTRACT FROM AUTHOR]

New pyridazino[4,5- b ]indol-4-ones and pyridazin-3(2 H )-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC 50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines. [ABSTRACT FROM AUTHOR]

We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine substituents. [ABSTRACT FROM AUTHOR]