Studies on the Synthesis, Anticonvulsant Activity, and the Structure-Activity Relationships of Phenyl Pyridazinones and their GABA Derivatives

In searching for effective anticonvulsant agents,fourteen 6-aryl-4.5-di- hydro-3(2H)pyridazinones.fifteen 6-aryl-3(2H)pyridazinones,and seventeen 3-GABA derivatives of 6-aryIpyridazines have been synthesized,and evaluated in mice for the ability to antagonize maximal electroshock seizure(MES).The ED_(50) values showed that 6-(2′,4′- dichlorophenyt)-3(2H)pyridazinone was the most potent anticonvulsant among these corn- pounds(ED_(50)=10.15 mg/kg).The structure-activity relationships of the aryl pyridazinones were studied.The result showed that:(1)the higher the value of the hydrophobic parameter л of the substituent on the phenyl ring.the more potent the anticonvulsant activity of the corn- pound.and(2)only the compounds with an electron withdrawing substituent on the phenyl ring exhibited appreciable anticonvulsant activity.

Synthesis of N-Aryl-2-(1′,6′-dihydro-6′-pyridazinone-3′-carbonyl) Thiosemicarbazides and Their Related Heterocyclic Compounds

Dihydro-3-hydrozinocarbonyl-6-pyridazinone(compound 2) were prepared from α-ketoglutaric acid and hydrazine hydrate. A series of N-aryl-2-(1′,6′-dihydro-6′-pyridazinone-3′-carbonyl) thiosemicarbazides 3a_3f were synthesized from the reaction of aryl isothiocyanates with compound 2. The terminal compounds 1,3,4-thiadiazole, 1,3,4-oxadiazole and 1,2,4-triazol-5-thione derivatives were cyclized from compounds 3a_3f. Their structures were confirmed by IR, 1H NMR, MS and elemental analyses.

An efficient chemo-and regioselective three-component synthesis of pyridazinones and phthalazinones using activated KSF

The first three-component and regioselective synthesis of pyridazinones and phthalazinones from arenes,anhydrides and ArNHNH;in the presence of efficient recyclable heterogeneous catalyst,montmorillonite-KSF,in high yield and short reaction time is reported.

Synthesis and Electronic Properties of 6-Chloro-2-diethylaminoethyl-3(2H)-pyridazinone

Chloro 2 diethylaminoethyl 3(2H) pyridazinone was synthesized by the reaction of 6 chloro 3(2H) pyridazinone and 2 diethylamionethyl chloride reaction in methylbenzene. Then the structure was characterized by means of 1H NMR, IR, UV. By the method of ab initio HF and density functional theory (DFT) B3LYP, the geometric structures of the reagent intermediate, the product and its isomer were optimized and their total energies were calculated. The properties for the frontier molecular orbitals and the rules for energy distribution were analyzed systematically. It was shown that the energy of the nitrogen alkyl compound is lower than that of the oxy alkyl compound and the former is stable than the latter . This result is in accordance with the fact that 6 chloro 2 diethylaminoethyl 3(2H) pyridazinone is synthesized by the reaction of \{6 chloride \}2 diethylaminoethyl 3(2H) pyridazinone and 2 diethylaminoethyl chloride.

Synthesis of Heterocycle Compounds Containing Two Pyridazinone Units

Four novel compounds containing two pyridazinone units attached to one benzene or pyridine ring, protected and deprotected 1,5-di[3（2H）-pyridazinon-6-yl]benzene and 2,6-di[3（2H）-pyridazinon-6-yl]pyridine were synthesized in eight steps, which provided a useful method for the preparation of pyridazinone derivatives via the Stetter and cyclization reactions. Their structures were characterized by ^1H NMR, ^13C NMR, and HRMS.

Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors

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 structureàactivity 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 Z 91.6%,at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

Design and synthesis of nitrogen-fused pyridazinone fluorescent probes and their application in biological imaging

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.