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Abstract: The design and synthesis of pyridazinone and phthalazinone derivatives are described. Newly synthesized compounds were tested on a panel of four kinases in order to evaluate their activity and potential selectivity. In addition, the promising compounds were tested on four cancer cell lines to examine cytotoxic effects. The compounds inhibited DYRK1A and GSK3 with different activity. SAR analysis and docking calculations were carried out to aid in the interpretation of the results. Taken together, our findings suggest that pyridazinone and phthalazinone scaffolds are interesting starting points for design of potent GSK3 and DYRK1A inhibitors. [Copyright &y& Elsevier]

Abstract: Azines, pyrazoles, and pyridazinones were isolated as the sole products in high yields (>97%) by grinding solid hydrazine (H3N+NHCO2 −) with di-carbonyl compounds or by their reaction in the absence of solvent. Neither catalysts nor additives were needed to promote the reactions. The solid-state and solvent-free reactions proceeded under ambient conditions and did not produce any wastes other than water and carbon dioxide. They are operationally easy, environmentally safe, and readily scalable, allowing for highly selective synthesis of compounds containing the hydrazine motif. [Copyright &y& Elsevier]

Abstract: We found a mild and efficient reaction condition for construction of a chiral 5-methyl-4,5-dihydropyridazin-3(2H)-one from a chiral β-methyl γ-ketocarboxylic acid via the corresponding acid hydrazide without racemization. Furthermore, we demonstrated that this two-step reaction can be attained by one-pot reaction. This method could be applied to various kinds of substrates because of the mild reaction conditions. [Copyright &y& Elsevier]

Abstract: We hereby report the synthesis of a novel class of compounds, 7-aminofuro- and 7-aminothieno[2,3-d]pyridazin-4(5H)-one and 4-aminophthalazin-1(2H)-ones starting from methyl 2-(2-methoxy-2-oxoethyl)furan- and thiophene-3-carboxylate and methyl 2-(2-methoxy-2-oxoethyl)benzoate. The ester functionalities connected directly to the aromatic ring were regiospecifically converted to the acid, whereas methylene groups were oxidized to the corresponding ketoesters. Reaction of the ketoesters with hydrazine provided the hydrazone derivatives. An intramolecular cyclization in the presence of thionyl chloride formed a fused pyridazinone skeleton. Hydrolysis of the remaining ester groups and transformation of the acid functionalities to the acyl azides followed by Curtius rearrangement gave the isocyanates. Reaction of the isocyanates with methanol and water produced urethane and aminopyridazinone derivatives, respectively. [Copyright &y& Elsevier]

Some new N-substituted pyridazinones and triazolo[4,3-b]pyridazinones were synthesized, respectively, by simple alkylation and 1,3-dipolar cycloaddition of pyridazin-3-one with nitrile imines. The regioselectivity of the reactions was ascertained by ¹H, 13C NMR spectroscopy and X-ray diffraction of the synthesized compounds. [ABSTRACT FROM AUTHOR]

In this study eighteen new N'-[(4-Substituephenyl)sulfonyl]-2-[4-(Substituephenyl)-piperazine]- 3(2H)-pyridazinone-2-yl acetohydrazide V derivatives were synthesized as acetylcholinesterase and butyrylcholinesterase inhibitors. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChe) inhibitory activity of V derivatives was measured using Ellman's method. Some of N'-[(substituted phenyl)sulfonyl]-2-(6-substituted-3(2H)-pyridazinone-2-yl)acetohydrazides V showed inhibitory activities close galantamine at 0.05 mM 0.1 mM and 0.2 mM concentrations. According to screening data, the analog of derivatives of V which possessed CF3 on para position of phenylsulfonyl ring improved anti-AChE activity. Also antimicrobial activity of the synthesized compounds have been evaluated. In general V Derivatives showed weak antibacterial activity when compared reference compounds. Also all the compounds are less potent than fluconazole against yeast like fungi. [ABSTRACT FROM AUTHOR]

The pyridazinone core has emerged as a leading structure for fighting inflammation, with low ulcerogenic effects. Moreover, easy functionalization of various ring positions of the pyridazinone core structure makes it an attractive synthetic and therapeutic target for the design and synthesis of anti-inflammatory agents. The present review surveys the recent advances of pyridazinone derivatives as potential anti-inflammatory agents to provide insights into the rational design of more effective anti-inflammatory pyridazinones., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

Many research groups have been interested in 3(2H)- pyridazinones for the development of potential analgesic and antiinflammatory agents. Stimulated by these findings, three 6-(mnitrophenyl)- 4-subtituted benzylidene-4,5-dihydropyridazin-3(2H)- ones (IVa-IVc) have been synthesized and evaluated for analgesic activity against hot plate method. Compounds IVa-IVc were prepared from 6-m-nitrophenyl-4,5-pyridazin-3(2H)-one by condensation with respective aldehydes. All compounds (IVa-IVc) having nitro phenyl and benzylidene groups at position 6 and 4 of the pyridazinone ring receptively. All compounds (IVa-IVc) showed significant analgesic activity when compared to control group and were found less potent than reference drug aspirin. [ABSTRACT FROM AUTHOR]

Eleven antipyrine/pyridazinone hybrids were synthesized and evaluated for their in vivo analgesic and anti-inflammatory activities by p-benzoquinone-induced writhing test and carrageenan-induced paw edema model, respectively. The test results indicated that compounds 6a, 6c, and 6d were equally or more potent analgesic and anti-inflammatory agents than aspirin and indomethacin, respectively. Side effects of the compounds were examined on gastric mucosa. Most of the compounds were found to be non-ulcerogenic under test conditions. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and structure-activity relationship studies of a series of compounds from imidazopyridazinone scaffold as PDE7 inhibitors are disclosed. Potent analogs such as compounds 7 (31nM), 8 (27nM), and 9 (12nM) were identified. The PDE selectivity and pharmacokinetic profile of compounds 7, 8 and 9 are also disclosed. The adequate CNS penetration of compound 7 in mice allowed it to be tested in the MPTP induced PD model and haloperidol induced catalepsy model to probe the differential pharmacology of PDE7 in the striatal pathway. [Copyright &y& Elsevier]

A series of seven heterocyclic compounds based on pyridazinone and thiopyridazinone moieties: 5-(2-chlorobenzyl)-6-methylpyridazin-3-one L1; 5-[(2-chlorobenzyl)hydroxyl)methyl]6-methylpyridazin-3-one L2; 5-(2-chlorobenzyl)-2,6-dimethylpyridazin-3-one L3; 5-(2-chlorobenzyl)-2-(hydroxyethyl)-6-methylpyridazin-3-one L4; ethyl-4-(2-chloro-benzyl)-3-methyl-6-oxopyridazin-1(6H)-yl)acetate L5; 5-(2-chlorobenzyl)-2-(hydroxyethyl)-6-methylpyridazin-3-thione L6, and ethyl-4-(2-chloro-benzyl)-3-methyl-6-thioxopyridazin-1(6H)-yl)acetate L7 were tested for the oxidation of catechol to o-quinone for miming microorganism in the O activation for electrophilic non substituted aromatic. The in situ generated Cu(II), Fe(II) and Zn(II) complexes of these ligands ( L1- L7) were examined for such catalytic activities. We found that all these substrates catalyze the oxidation reaction of catechol to o-quinone with the presence of atmospheric dioxygen. The rates of this oxidation depend on two parameters: the nature of the ligand and the nature of ion salts. We found that the combination of L7 [ Cu( CH COO)] leads to the fastest catalytic processes. [ABSTRACT FROM AUTHOR]

Rh2(OAc)4-Catalyzed decomposition of diazo esters in the presence of perfluoroalkyl- or perfluoroaryl-substituted silyl enol ethers smoothly provided the corresponding alkyl 2-siloxycyclopropanecarboxylates in very good yields. The generated donoracceptor cyclopropanes are equivalents of γ-oxo esters, which we demonstrated by their one-pot transformations to yield fluorine-containing heterocycles. A reductive procedure selectively afforded perfluoroalkyl-substituted γ-hydroxy esters or γ-lactones. The treatment of the donoracceptor cyclopropanes with hydrazine or phenylhydrazine afforded a series of perfluoroalkyl- and perfluoroaryl-substituted 4,5-dihydropyridazin-3(2 H)-ones. [ABSTRACT FROM AUTHOR]

A series of new 4-(aryl/heteroaryl-2-ylmethyl)-6-phenyl-2-[3-(4-substituted piperazine-1-yl)propyl] pyridazin-3( 2H)-one derivatives were synthesized. The structures of the compounds were confirmed by IR, H NMR, and mass spectral data. All the compounds were evaluated for their cytotoxicity toward five human cancer cell lines of different origins viz; HeLa (Cervical), SKBR3 (Breast), HCT116 (Colon), A375 (Skin) & H1299 (Lung) at different concentrations and the IC values were determined. HCT116 and HeLa are the most sensitive against the compounds studied. One of them displayed moderate cytotoxicity against SKBR3. Majority of the compounds exhibited good to moderate activity. [ABSTRACT FROM AUTHOR]

Abstract: 5-Iodo- and 4,5-dibromo-2-methylpyridazin-3(2H)-ones were aminocarbonylated in the presence of various amines including amino acid methyl esters in a palladium-catalysed reaction. The iodo derivative afforded the corresponding amides with complete conversion and high isolated yields. The dibromo derivative has shown unexpectedly high reactivity in this reaction, resulting in 4,5-dicarboxamides using primary amines as N-nucleophiles. Monoaminocarbonylation has not been observed, i.e., neither 4-bromo-5-carboxamide nor 4-carboxamido-5-bromo derivatives have been formed. However, the use of secondary amines such as piperidine and morpholine resulted in the formations of mixtures of amino-substituted bromopyridazinones. That is, no carbon monoxide insertion took place in these cases. Some mechanistic details of the formation of aminocarbonylation and amination products are also discussed. [Copyright &y& Elsevier]

Abstract: A detailed structure–activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model. [Copyright &y& Elsevier]

Abstract: PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K i value of <1nM and an EC50 value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ). [Copyright &y& Elsevier]

Abstract: The structure–activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy. [Copyright &y& Elsevier]

A new one-pot strategy for the synthesis of phthalazines and pyridazino-aromatics starting from aromatic aldehydes has been developed. A variety of substituents ranging from electron withdrawing to donating is tolerated furnishing the desired 1,2-diazine in good to excellent yields. The products have been applied to the bidentate Lewis acid catalyzed inverse electron-demand Diels–Alder (IEDDA) reaction opening a novel two-step entry into substituted naphthalenes, such as Naproxen. [ABSTRACT FROM AUTHOR]

Abstract: The first ultrasound-promoted multicomponent synthesis of pyridazinones and phthalazinones from arenes, cyclic anhydrides and ArNHNH2 in the presence of an efficient recyclable catalyst, [bmim]Br/AlCl3, in high yield and short reaction time is reported. [Copyright &y& Elsevier]

Abstract: A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities. [Copyright &y& Elsevier]

3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either 2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino-6-phenyl-5-ptolyl- azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly, other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles 2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3- phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo- 2,6-dihydropyrido[3,2-c]cinnoline-3-carboxylate (11), via a novel 6π-electrocyclization pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a-c to yield pyridazinones 13a-c. [ABSTRACT FROM AUTHOR]

Abstract: In this study, eighteen new isoxazolo[4,5-d]pyridazin-4(5H)-one derivatives possessing either a 1,3,4-thiadiazole or a 1,2,4-triazole-5-thione moiety were synthesized and tested for anti-inflammatory activity in vitro (COX-1/COX-2, 5-LOX) and in vivo (rat paw edema assay). Compounds 15, 16, 25, 26 and 28–30 showed dual COX-2 (IC50’s in the 2.1–10.9μM range), and 5-LOX (IC50’s in the 6.3–63.5μM range) inhibitory activity. When administered orally to rats, dual COX-2/5-LOX inhibitors showed higher anti-inflammatory activity in vivo (30–45% reduction of the inflammatory response) than the reference drug ibuprofen (18%). Among dual COX-2/5-LOX inhibitors, the most potent compound (28) exhibited the best anti-inflammatory profile by inhibiting both COX-2 (IC50 =2.1μM) and 5-LOX (IC50 =6.3μM) enzymes. We investigated the binding interactions of compound 28 by an enzyme–ligand molecular modeling (docking) studies, which showed favorable binding interactions in both COX-2 and 5-LOX active sites. Furthermore, the dual acting COX-2/5-LOX compound 28 exhibited a superior gastrointestinal safety profile (ulcer index=0.25) compared to the reference drug ibuprofen (UI=7.0) when administered orally at the same molar dose. These observations suggest that isoxazolo[4,5-d]pyridazin-4(5H)-one analogs represent a new scaffold to design potent, effective, and safe anti-inflammatory agents possessing dual COX-2/5-LOX inhibitory activity. [Copyright &y& Elsevier]

Absract: A series of novel pyridazinone derivatives bearing benzenesulfonamide moiety (2a–h) has been synthesized by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Five derivatives (2a, 2b, 2d, 2g and 2h) were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute. The 2h showed remarkable activity against SR (leukemia) and NCI-H522 (non-small cell lung) with a GI50 value of less than 0.1 μM. It also displayed good activity against leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-small cell lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-620), CNS (SF-295), melanoma (MALME-3M, M14, MDA-MB-435 SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7) cancer cell lines with a GI50 less than 1.0 μM. The acute toxicity study of 2h indicated that it is well tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. The 2h may possibly be used as lead compound for developing new anticancer agents. [Copyright &y& Elsevier]

To access useful heterocycles in medicinal chemistry such as pyridazinones, dihydropyrimidinones, and dihydropyrimidinthiones, a “green” mild and highly efficient one-pot triple cascade was developed involving a Claisen–decarboxylation, electrophilic reaction, and subsequent heterocyclization. In addition, indazoles and benzofurans could also be constructed via a double cascade. To develop the cascade process, a direct Claisen–decarboxylation reaction was firstly optimized. This reaction can then couple with electrophilic reactions including alkylation, Michael addition or aldol reaction to enable the preparation of various aryl ketones in a one-pot fashion. [ABSTRACT FROM AUTHOR]

Abstract: (−)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo. [Copyright &y& Elsevier]

Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones ( 2a-g) were synthesized by the condensation of appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Structure of all compounds have been elucidated by elemental analysis, IR, 1H NMR, 13C NMR, DEPT and MS spectrscopy. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5 h). Two other compounds 2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5 h). These compounds ( 2b, 2d and 2g) did not produce any ulceration in gastric region. [ABSTRACT FROM AUTHOR]

A series of 1,2,4-triazolo[3′,4′:6,1]pyridazino[4,3- e][1,3,4]thiadiazines have been synthesized by intermolecular cycli­zation of a hydrazide derivative with various triethyl ortho­esters. The antibacterial activity of various derivatives of this new heterocyclic system was evaluated. [ABSTRACT FROM AUTHOR]

Abstract: Structure–activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles. [Copyright &y& Elsevier]

Abstract: Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5-one (9a) which was shown to be a competitive inhibitor with a Ki value of 0.11 μM. Replacing the methyl group in the 3-position with a meta–CF3–phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c]pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity. [Copyright &y& Elsevier]

Abstract: A series of pyridazinone–phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H3R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H3R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model. [Copyright &y& Elsevier]

Abstract: Three series of novel 4,5-fused pyridazinones were synthesized as histamine H3 receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H3 receptors, and showed potent antagonist and full inverse agonist activity in functional assays. [Copyright &y& Elsevier]

Abstract: In this Letter, we report on diarylpyridinone, diarylpyridazinone and diarylphthalazinone analogs as potential inhibitors of HIV-1 nonnucleoside reverse transcriptase (NNRTIs). The most promising compounds in these series are three diarylpyridazinones 25a, 25l and 25n which demonstrated submicromolar activity against wild-type HIV-1 and moderate activity against the single mutant strain Ba-L V106A. [Copyright &y& Elsevier]

A series of pyridazinone derivatives ( 19-34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48-77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone ( 26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone ( 20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen. [ABSTRACT FROM AUTHOR]

Abstract: A series of N2-{2-[4-aryl(benzyl)-1-piperazinyl(piperidinyl)]ethyl}pyrrolo[3,4-d]pyridazinones 4 and related derivatives 5 were synthesized as potential analgesic agents. The structures of the new compounds were elucidated by micro, spectral and X-ray analysis. Analgesic activity of the compounds was investigated in the phenylbenzoquinone induced ‘writhing’ and ‘hot plate’ test in mice and at radioligand binding assay. At ‘writhing’ test all compounds, without exception, were more active than acetylsalicylic acid (ASA) with ED50 values ranging from 0.04 to 11 mg/kg (i.p.) (ED50 for ASA – 39.15 mg/kg). Analgesic effect at the ‘hot plate’ test was observed for three compounds 4c,e,f at the dose 3–5 times higher then that of morphine (ED50-3.39 mg/kg). At radioligand binding assay of 4c,e,f only compound 4f exhibited affinity for the μ-opioid receptors similar to that of Tramadol. The acute toxicity of the pyrrolopyridazinones 4, 5 were also studied and non toxic effect was observed at the 2000 mg/kg (5a 1420 mg/kg) i.p. dose level. On the basis of the available pharmacological data S-A relationship is discussed. The preferred conformational characteristic of 4, taken 4c as an example, was also described. [Copyright &y& Elsevier]

Norflurazon and simazine are pre-emergent herbicides detected frequently in surface water associated with South Florida agricultural canals and drainage water. This study investigated the potential use of a 1.34 ha constructed wetland for removing these herbicides from surface water. The total length of the wetland was 400 m and width was 35 m. A surface water flow rate of 740 L/min was maintained in the system using a pump. The plant community within the system consisted primarily of Panicum repens, Alternanthera philoxeroides, and Bacopa caroliniana. Norflurazon and simazine, derived from commercial formulations, were injected (51.1 g active ingredient each) directly into the water pumped into the wetland over a 2 h period. Water samples were collected from the wetland upstream of the dosing system at 3 h intervals from the beginning through 360 h and at the exit point at 1, 2, and 3 h intervals for the periods of 0-24, 25-48 and 49-360 h after dosing, respectively. The herbicides were extracted using C-18 cartridges and were analyzed by GC-TSD. The total mass of each herbicide discharged from the system was estimated by multiplying the concentration by the total volume discharged during the sampled period. Neither herbicide was detected in the inflow water during the entire study. Norflurazon was first detected at the exit 19 h after dosing and simazine after 23 h. Discharge patterns of the two herbicides differed dramatically. Norflurazon tended to bleed off from the wetland with no distinct peak concentration. However, the mobile fraction of simazine was discharged over a 58 h period. Mean/maximum/median detectable concentrations of the herbicides were 3.9 ± 1.7/8.1/3.4 μg L for norflurazon, and 11.9 ± 6.8/23.6/12.0 μg L for simazine, respectively. The total masses of norflurazon and simazine discharged from the exit during the 15 day study were 51.7 and 26.9 g, indicating 0% and 47.4% removal from the surface water by the system. [ABSTRACT FROM AUTHOR]

Abstract: Pyridazinone 1 was recently reported as a potent H3R antagonist with good drug-like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified. [Copyright &y& Elsevier]

Background: Many synthetic heterocyclic compounds are known to have different biological activities. Pyridazine and its derivatives are the important six membered heterocyclic compounds containing two N-hetero atoms. The pyridazine moiety is an important structural feature of many biologically active compounds. Pyridazine derivatives show diverse pharmacological properties. Aims and Objectives of the Study: The goal of this study, Pyridazine hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds also. On the basis of its important in reported literature, we synthesized the 6-(Biphenyl-4-yl)-2-[2-(indol- 1-yl)ethyl]-4,5-dihydropyridazin-3(2H)-one from 6-(Biphenyl-4-yl)-2-[2-(indol-1-yl) ethyl]-4,5-dihydro pyridazin-3(2H)-one in single step or pot reaction. Results: The important Observations and concrete implications of the study. The result showed that the compound 6-(Biphenyl-4-yl)-2-[2-(indol-1-yl) ethyl]-4,5-dihydropyridazin-3(2H)- one was not prepared by this method. The synthesis of compound has been confirmed by the spectral analysis namely IR, 1H NMR and Mass spectroscopy. [ABSTRACT FROM AUTHOR]

The first one-pot synthesis of pyridazinones and phthalazinones from arenes, cyclic anhydrides, and ArNHNH2 in the presence of efficient recyclable heterogeneous catalyst, HY-zeolite, in high yield and short reaction time is reported. J. Heterocyclic Chem., (2011). [ABSTRACT FROM AUTHOR]

Abstract: Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure–activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7′ in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3′-centre to C-4′ strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast. [Copyright &y& Elsevier]

Abstract: A novel series of pyridazinone analogs has been developed as potent β-1,3-glucan synthase inhibitors through structure–activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans. [Copyright &y& Elsevier]

[image omitted] Phenacyl-malononitrile derivatives 1a and b react with dimethylformamide dimethylacetal (DMFDMA) in refluxing toluene to afford the enaminones 2a and b respectively. Compounds 2a and 2b react with the hydrazine hydrate 3a and phenyl hydrazine 3b in refluxing ethanol to afford the pyridazine derivatives 5a-d, presumably via the intermediates 4. Compounds 5a-d, react with hydrazine hydrate 3a to afford the pyridazino[4,5-d]pyridazines 6a-d respectively. The pyridazines 5a and b and the pyridazino[4,5-d] pyridazines 6a and b could be oxidized into the full aromatic systems 7a and b and 8a and b respectively. Compounds 7a and b react also with hydrazine hydrate 3a to afford 8a and b respectively. [ABSTRACT FROM AUTHOR]

Abstract: A series of planar chiral ferroceno[d]pyridazinones was prepared by hydrazine-mediated cyclisations of (Sp)-2-formylferrocenoyl fluoride obtained in two steps from (2S,4S)-4-(methoxymethyl)-2-ferrocenyl-1,3-dioxane. Further derivatives based on the novel heterocyclic scaffold were resulted by means of the facile N-alkylation reactions carried out on the easily accessible fused product derived from the hydrazine-mediated cyclisation. Upon treatment with hydrazine (Sp)-2-formylferroce carboxylic acid, the precursor of the acid fluoride with enhanced reactivity, afforded a dimeric azine avoiding cyclisation. The spectacular difference between the experimentally observed reactivity of the bifunctional formylferrocenes was disclosed by comparative DFT analysis of the assumed hydrazone- and hydrazide intermediates with different values of LUMO energy associated with different conformation. The structures of the new compounds were established by IR and NMR spectroscopy, including HMQC, HMBC and DNOE measurements. [Copyright &y& Elsevier]

In the present study, six new derivatives of Pyridazinone were synthesized and evaluate their anti-bacterial activity. The experimental work involves the synthesis of benzoyl propionic acid (a), then 6-phenyl-2,3,4,5- tetrahydro pyridazin-3-one (b) which was then condensed with various aldehydes to form respective derivatives. All the synthesized compounds were identified by IR, 1HNMR and antimicrobial activity was performed on the compounds synthesized against Staphylococcus aureus (MTCC 737), Staphylococcus epidermidis (MTCC 3615), Pseudomonas aeruginosa (MTCC 424) and Escherichia coli (MTCC 1687). [ABSTRACT FROM AUTHOR]

A “click and activate” strategy was designed and executed in a four-component, stepwise condensation that led to a trisubstituted triazolyl-pyridazinone library. This one-pot process included regioselective azide substitution at 2-substituted-4,5-dichloropyridazinones, followed by a Cu(I) catalyzed triazole formation which triggered subsequent nucleophilic substitution at the neighboring position to achieve three points of diversity. [ABSTRACT FROM AUTHOR]

Abstract: A structure–activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a β-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection. [Copyright &y& Elsevier]

7-Phenyl-3,4,8,9-tetrahydro-2H-pyridazino[1,6-a][1,3,5]triazin-2-imine was synthesized by a sequence of reactions starting from 6-phenyl-4,5-dihydropyridazin-3(2H)-one 1. The structure of the title compound 3 was established on the basis of IR, ¹H-NMR, 13C-NMR and mass spectral data. [ABSTRACT FROM AUTHOR]

[image omitted] A diastereospecific synthesis of N-vinyl heterocyclic compounds is described from a reaction of dialkyl acetylenedicarboxylate and N-H heterocyclic compounds, such as phthalimide, saccharin, 3(2H)-pyridazinone, isatin, maleimide, 2,4-thiazolidinedione, 2-benzoxazolinione and 6-chloro-2-benzoxazolinione, in the presence of triphenylarsine as an efficient catalyst, in excellent yield. The presented one-pot method is simple and effective with mild conditions. [ABSTRACT FROM AUTHOR]

Abstract: A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a–4u) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k showed appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol. [ABSTRACT FROM AUTHOR]

With the aim to develop novel HIV-1 integrase inhibitors, we obtained a set of condensed ring systems based on the furo[2,3-h]cinnolin-3(2H)-one and pyridazino[3,4-f]cinnolin-3-ol scaffolds bearing a potential chelating pharmacophore, which can be involved in the inhibition mechanism of the enzyme. Herein, we report the design, synthesis, structural investigation and preliminary biological results of these heteroaromatic systems. [ABSTRACT FROM AUTHOR]