Pyridazine Ring Research Articles

Electronic and Photophysical Properties of ReI(CO)3Br Complexes Modulated by Pyrazolyl–Pyridazine Ligands

The direct reaction of a series of substituted (1H-pyrazol-1-yl)pyridazine (LI: 6-(1H-pyrazolyl)pyridazine; LII: 3-chloro-6-(1H-pyrazole-1-yl)-pyridazine; LIII: 6-(1H-3,5-dimethylpyrazolyl)pyridazine-3-carboxylic acid; LIV: 3,6-bis-N-pyrazolyl-pyridazine; and LV: 3,6-bis-N-3-methylpyrazolyl-pyridazine) with the bromotricarbonyl(tetrahydrofuran)-rhenium(I) dimer leads to the monometallic complexes [(LX)Re(CO)3Br] (I–V), which displays a nonregular octahedral geometry around the ReI center and a fac-isomerism for the carbonyl groups, whereas pyridazine and pyrazolyl rings remain highly coplanar after coordination to rhenium. Cyclic voltammetry shows one irreversible oxidation and one irreversible reduction for each compound as measured in N,N-dimethylformamide. Oxidation ranges from 0.94 V for III to 1.04 V for I and have been attributed to the ReI/ReII couple. In contrast, the reductions are ligand centered, ranging from −1.64 V for II to −1.90 V for III and V. Density functional theory calculations on the...

Synthesis and structural studies of 3,6-disubstituted-bis-1,2,4-triazolo-[4,3-b][3′,4′-f]pyridazines

Synthesis of a series of 3,6-disubstituted-bis-1,2,4-triazolo-[4,3-b][3′,4′-f]pyridazines (4) was accomplished by the oxidative intramolecular cyclization of 6-arylidenehydrazino-3-aryl-1,2,4-triazolo[4,3-b]pyridazine (3) using iodobenzene diacetate (IBD), as a green oxidant, in dichloromethane at room temperature. The compounds 3 and 4 were characterized by IR, NMR (1H and13C), mass spectral data and elemental analyses. X-ray crystal analysis of sterically strained 3,6-di-(2′-fluorophenyl)-bis-1,2,4-triazolo-[4,3-b][3′,4′-f]pyridazine 4f and 3,6-di-(4′-fluorophenyl)-bis-1,2,4-triazolo-[4,3-b][3′,4′-f]pyridazine 4g indicated that pyridazine ring has twisted conformation leading to nonplanar tricyclic core. Both compounds crystallized in orthorhombic P212121 space group, containing one single molecule per asymmetric unit. The studies reveal that the compound 4f is associated with weak, centrosymmetric F⋯F interactions (distance of 2.882(3) Å), with cis geometry, between adjacent molecules which are responsible for the formation of chains along a axis. Additionally, compounds 4 were screened for their cytotoxic activity against the human cervical carcinoma (HeLa) cell line using MTT assay, however, with not much significant activity.

Synthesis of Two Key Fragments of the Complex Polyhalogenated Marine Meroterpenoid Azamerone.

A concise route toward two advanced fragments in the context of the total synthesis of the unique natural product azamerone is reported. Key synthetic features include the enantioselective synthesis of an epoxysilane and its Lewis-acid-induced cyclization and the installation of the pyridazine ring via a formylation/condensation sequence. This route provides strategic insights into the chemistry of phthalazinediols, facilitating synthetic approaches toward this class of natural products.

A Review on Pyridazinone Ring Containing Various Cardioactive Agents

In this work, some pyridazinones were studied for their cardioactive activity. These compounds showed significant cardio-active action with respect to the regular used drugs. However, it was found that the existence of the pyridazine ring is a crucial necessity in the structure of these pyridazinonecompounds to show the improved cardioactive activities. It was also understood that the substitution of the different group on the pyridazinone ring with other related bioisosteres or isosteres along with the existence of pyridazine ring may provide better cardioactive compounds. Pyridazinoneis, a component of various cardio-active agents, which are in uses clinically or in clinical trials. These contain pimobendan, indolidan, levosimendan, imazodan, CI-930, meribendan, bemoradan, senazodan, siguazodan, amipizone, prinoxodan, Y-590, SK&F-93741, SKF 95654, NSP-805, NSP-804 and KF 15232. This study briefly reviews the pyridazinone ring for the progress of new cardio-active drugs.

Imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazinone as a new scaffold of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study

New series of thiazolo[4,5-d]pyridazin and imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC50 0.05 and 0.06 μM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC50 0.32 and 0.46 μM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N1-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23–25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2′,1′:2,3]-thiazolo[4,5-d]pyridazine (43–54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors.

Synthesis of Pyridazine and Pyrrole Analogues of 2‐Aminotetralin as Potential Dopaminergics

Syntheses of pyridazine and pyrrole analogues of 2‐aminotetralin starting from 3‐cyclohexene‐1‐carboxylic acid are reported. All syntheses involve the following key steps: Curtius rearrangement for amine functionality, inverse electron demand Diels–Alder addition with 1,2,4,5‐tetrazine for pyridazine ring synthesis, and pyridazine‐to‐pyrrole ring contraction for pyrrole ring formation.

Effect of substituted methyl group by phenyl group in pyridazine ring on the corrosion inhibition of mild steel in 1.0 M HCl

PurposeThe purpose of this paper is to study the inhibition effect of (6-phenyl-3-oxopyridazin-2-yl) acetohydrazide (GP4) on the corrosion of mild steel in acidic medium by gravimetric measurements, potentiodynamic polarization, and electrochemical impedance spectroscopy (EIS).Design/methodology/approachWeight loss measurements, potentiodynamic tests and EIS were performed during this study.Findings(6-phenyl-3-oxopyridazin-2-yl) acetohydrazide (GP4) was found to be a very efficient inhibitor for mild steel in 1.0 M HCl solution, reaching about 85 per cent with inhibitor concentration 1.0 × 10-3 M at 303 K.Practical implications(6-phenyl-3-oxopyridazin-2-yl) acetohydrazide (GP4) was found to play an important role in the corrosion inhibition of mild steel in acidic solution.Originality/valueThis paper is intended to be added to the family of pyridazine derivatives which are highly efficient inhibitors and can be used in the area of corrosion prevention and control.

Synthesis of Furo[2,3-c]pyridazines via Tandem Transition-Metal Catalysis.

A general and efficient catalytic approach to synthesis of the furo[2,3-c]pyridazine ring system is reported. Building on the easily accessible 2-bromo-3-aminopyridizinone skeleton, a tandem Sonogashira coupling-cycloisomerization provides ready access to functionalized furopyridazines. A wide functional group tolerance was observed in the tandem reaction, which proceeds in high yield in 1-3 h. The structure of the heterocyclic ring system was confirmed through single-crystal X-ray crystallography.

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. Previously small molecule inhibitors of human DNA ligases were identified using a structure-based approach. Three of these inhibitors, L82, a DNA ligase I (LigI)-selective inhibitor, and L67, an inhibitor of LigI and DNA ligases III (LigIII), and L189, an inhibitor of all three human DNA ligases, have related structures that are composed of two 6-member aromatic rings separated by different linkers. Here we have performed a structure-activity analysis to identify determinants of activity and selectivity. The majority of the LigI-selective inhibitors had a pyridazine ring whereas the LigI/III- and LigIII-selective inhibitors did not. In addition, the aromatic rings in LigI-selective inhibitors had either arylhydrazone or acylhydrazone, but not vinyl linkers. Among the LigI-selective inhibitors, L82-G17 exhibited increased activity against and selectivity for LigI compared with L82. Notably. L82-G17 is an uncompetitive inhibitor of the third step of the ligation reaction, phosphodiester bond formation. Cells expressing LigI were more sensitive to L82-G17 than isogenic LIG1 null cells. Furthermore, cells lacking nuclear LigIIIα, which can substitute for LigI in DNA replication, were also more sensitive to L82-G17 than isogenic parental cells. Together, our results demonstrate that L82-G17 is a LigI-selective inhibitor with utility as a probe of the catalytic activity and cellular functions of LigI and provide a framework for the future design of DNA ligase inhibitors.

S.12.04 - A novel approach to map induced activation of neuronal networks using chemogenetics and functional neuroimaging

The effects of four pyridazine derivatives namely, 2-(6-chloropyridazin-3-yl)-2-phenylacetonitrile (P1), 3-(6-chloro-3-pyridazinyl)-1H-indole (P2), 4-(6-chloropyridazin-3-yl)benzoic acid (P3) and 3-(6-chloropyridazin-3-yl)benzoic acid (P4) on electrochemical dissolution of mild steel in 1 M HCl were studied using electrochemical, spectroscopic, and theoretical computational chemistry techniques. The inhibition efficiency increases with increasing concentration of the inhibitors and the shift in corrosion potentials obtained revealed that the compounds are mixed-type inhibitors and steel dissolution was found to be a charge transfer process with the steel/electrolyte interface showed pseudo-capacitive behaviour. P1 and P2 showed the best protection performances for mild steel in the studied medium, attributable to the presence of more nitrogen atoms and unsaturated groups in their molecules compared to P3 and P4. The experimental adsorption data obeyed the Langmuir and Temkin isotherm models and was found to involve both physisorption and chemisorption. Spectroscopic studies revealed that the inhibitor molecules interact chemically with mild steel and the pyridazine ring is actively involved in these interactions. Quantum chemical calculations also showed that pyridazine ring has the tendency of interacting with metallic atoms via both forward and backward donations. Molecular dynamic simulation revealed that the molecules can adsorb strongly onto the surface of iron in a near flat orientation.

Blue Fluorescence from BF2 Complexes of N,O-Benzamide Ligands: Synthesis, Structure, and Photophysical Properties.

Small molecules having intense luminescence properties are required to promote biological and organic material applications. We prepared five types of benzamides having pyridine, pyridazine, pyrazine, and pyrimidine rings and successfully converted them into three types of the difluoroboronated complexes, Py@BAs, as novel blue fluorophores. Py@BA having a pyridine moiety (2-Py@BA) showed no fluorescence in solution, whereas Py@BAs of pyridazine and pyrazine moieties (2,3-Py@BA and 2,5-Py@BA, respectively) emitted blue fluorescence with quantum yields of ca. 0.1. Transient absorption measurements using laser flash photolysis of the Py@BAs revealed the triplet formation of 2,3- and 2,5-Py@BAs, while little transient signal was observed for 2-Py@BA. Therefore, the deactivation processes from the lowest excited singlet state of fluorescent 2,3- and 2,5-Py@BAs consist of fluorescence and intersystem crossing to the triplet state while that of the nonfluorescent Py@BA is governed almost entirely by internal conversion to the ground state. Conversely, in the solid state, 2-Py@BA emitted intense fluorescence with a fluorescence quantum yield as high as 0.66, whereas 2,3- and 2,5-Py@BAs showed fluorescence with quantum yields of ca. 0.2. The crystal structure of 2-Py@BA took a herringbone packing motif, whereas those for 2,3- and 2,5-Py@BAs were two-dimensional sheetlike. On the basis of the difference in crystal structures, the emission mechanism in the solid state was discussed.

Transforming Polybutadiene with Tetrazine Click Chemistry into Antioxidant Foams That Fluoresce with Oxidation

The extent to which oxidative degradation of macromolecules can be delayed is generally limited by the low solubility of antioxidants in most polymers. This can be surmounted by synthesizing macromolecules with covalently attached antioxidant functionalities, but these are frequently expensive. Here, we demonstrate a simple click modification of polybutadienes (PDB) with 3,6-dichloro-1,2,4,5-tetrazine (DCT) that, in addition to modifying and stiffening the polymer chains, releases nitrogen gas to foam the solidifying polymers and generates dihydropyridazine groups that transform them into macromolecular antioxidants. Tetrazines react by a cycloaddition/cycloreversion reaction (Carboni–Lindsey reaction) with the C═C bonds to install 1,4-dihydropyridazine groups that increase the mass and rigidity of the butadiene macromolecules. The 1,4-dihydropyridazine group is an effective antioxidant that donates two hydrogen atoms per ring to combine with radicals and forms an aromatic pyridazine ring whose white fluo...

Inhibition Mechanisms of a Pyridazine-Based Amyloid Inhibitor: As a β-Sheet Destabilizer and a Helix Bridge Maker.

Conformational diseases have been investigated extensively in recent years; as a result, a number of drug candidates have been introduced as amyloid inhibitors; however, no effective therapies have been put forward. RS-0406 with pyridazine as its core chemical structure has so far shown promising results in inhibiting amyloid formation. In the present work, using molecular dynamics, we undertook the investigation of RS-0406 interactions with U-shaped Aβ1-42 and Aβ1-40 pentamers, Aβ1-42 monomers, and double-horseshoe-like Aβ1-42. To set better parameters for the small molecule, experimental and computational log P values were obtained. In addition, an analogue of RS-0406 was also simulated for comparison. The results indicate that RS-0406 may inhibit amyloid formation exploiting two different mechanisms. One mechanism includes stabilizing the α helix, in the monomer peptide, by binding to the flanking sites of the amyloidogenic region. The second mechanism mediates through interaction of the small molecules near the amyloidogenic regions, leading to destabilization of the β-sheets in both the U-shaped and the S-shaped fibril. Notably, a persistent interaction between the imidazole ring of His14 from an S-shaped structure and the pyridazine ring of RS-0406 was observed. The unique structural properties of RS-0406, including aromaticity, H-bonding capability, flexibility, and symmetry, allow the small molecule to noticeably affect amyloid formation.

3-Methyl-5,6-diphenyl-1H-pyrazolo[1,2-a]cinnolin-1-one

The asymmetric unit of the title compound, C24H18N2O, comprises two crystallographically independent molecules (AandB), with slightly different conformations. In each molecule, there is an intramolecular C—H...O hydrogen bond forming anS(6) ring motif. The pyridazine rings of the pyrazolo[1,2-a]cinnoline units have screw-boat conformations. Their mean planes are inclined to the phenyl rings by 83.81 (8) and 74.19 (8)° in moleculeA, and 89.72 (8) and 71.07 (8)° in moleculeB. In the crystal, theAandBmolecules are linked by a pair of C—H...O hydrogen bonds, forming an A–B dimer with anR22(14) ring motif. These dimers are linked by further C—H...O hydrogen bonds, forming ribbons propagating along theb-axis direction. The ribbons are linked by a number of C—H...π interactions, forming a three-dimensional structure.

Synthesis of Novel Compounds with a Combination of Pyridazine, Pyrazole and 1,3,5-Triazine Rings and Preliminary Evaluation of Their Plant Growth Stimulant Activity

The syntheses of a series of novel compounds with a combination of pyrazole and pyridazine rings and their corresponding pyrazolyl-1-N-substituted derivatives were carried out. These rings are connected through the oxygen atom and oxoethoxy or oxoethyl moieties. At preliminary screening the synthesised compounds have shown pronounced plant growth stimulant activity. The most active compounds are being preparing for deeper studies and further field trials.

4-Chloro-5-(morpholin-4-yl)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]pyridazin-3(2H)-one

In the title compound, C17H16ClN5O3, the phenyl and the oxadiazole rings are almost coplanar, subtending a dihedral angle of 4.34 (19)°. These rings lie almost normal to the pyridazine ring, making dihedral angles of 87.35 (16) and 89.06 (15)°, respectively. The morpholine ring has the usual chair conformation and its mean plane is inclined to the pyridazine ring by 39.45 (17)°. There is a short intramolecular C—H...Cl contact present. In the crystal, molecules are linked by bifurcated C—(H,H)...O hydrogen bonds and a C—H...N hydrogen bond, forming layers parallel to the ab plane.

Experimental and theoretical investigation of the inhibitory effect of new pyridazine derivatives for the corrosion of mild steel in 1 M HCl

The effects of four pyridazine derivatives namely, 2-(6-chloropyridazin-3-yl)-2-phenylacetonitrile (P1), 3-(6-chloro-3-pyridazinyl)-1H-indole (P2), 4-(6-chloropyridazin-3-yl)benzoic acid (P3) and 3-(6-chloropyridazin-3-yl)benzoic acid (P4) on electrochemical dissolution of mild steel in 1 M HCl were studied using electrochemical, spectroscopic, and theoretical computational chemistry techniques. The inhibition efficiency increases with increasing concentration of the inhibitors and the shift in corrosion potentials obtained revealed that the compounds are mixed-type inhibitors and steel dissolution was found to be a charge transfer process with the steel/electrolyte interface showed pseudo-capacitive behaviour. P1 and P2 showed the best protection performances for mild steel in the studied medium, attributable to the presence of more nitrogen atoms and unsaturated groups in their molecules compared to P3 and P4. The experimental adsorption data obeyed the Langmuir and Temkin isotherm models and was found to involve both physisorption and chemisorption. Spectroscopic studies revealed that the inhibitor molecules interact chemically with mild steel and the pyridazine ring is actively involved in these interactions. Quantum chemical calculations also showed that pyridazine ring has the tendency of interacting with metallic atoms via both forward and backward donations. Molecular dynamic simulation revealed that the molecules can adsorb strongly onto the surface of iron in a near flat orientation.

Synthesis and biological activity of pyridazine amides, hydrazones and hydrazides.

Optimization studies on compounds initially designed to be herbicides led to the discovery of a series of [6-(3-pyridyl)pyridazin-3-yl]amides exhibiting aphicidal properties. Systematic modifications of the amide moiety as well as the pyridine and pyridazine rings were carried out to determine if these changes could improve insecticidal potency. Structure-activity relationship (SAR) studies showed that changes to the pyridine and pyridazine rings generally resulted in a significant loss of insecticidal potency against green peach aphids [Myzus persicae (Sulzer)] and cotton aphids [(Aphis gossypii (Glover)]. However, replacement of the amide moiety with hydrazines, hydrazones, or hydrazides appeared to be tolerated, with small aliphatic substituents being especially potent. A series of aphicidal [6-(3-pyridyl)pyridazin-3-yl]amides were discovered as a result of random screening of compounds that were intially investigated as herbicides. Follow-up studies of the structure-activity relationship of these [6-(3-pyridyl)pyridazin-3-yl]amides showed that biosteric replacement of the amide moiety was widely tolerated suggesting that further opportunities for exploitation may exist for this new area of insecticidal chemistry. Insecticidal efficacy from the original hit, compound 1, to the efficacy of compound 14 produced greater than 10-fold potency improvement against Aphis gossypii and greater than 14-fold potency improvement against Myzus persicae. © 2016 Society of Chemical Industry.

Polysubstituted and ring-fused pyridazine systems from tetrafluoropyridazine

Tetrafluoropyridazine 1 reacts with a range of oxygen-, nitrogen-, sulfur- and carbon-centred nucleophiles to give, in general, products 2 arising from substitution of fluorine para to ring nitrogen. Subsequent reaction of the trifluoropyridazine derivatives 2 gave a range of 4,5-di- and tri-substituted products 3 and 6. Related reactions of tetrafluoropyridazine 1 with difunctional nucleophiles gave [6,6]-, [5,6]- and [6,5,6]-polycyclic ring fused pyridazine scaffolds 4 and 9. Further functionalisation of scaffolds 4 by nucleophlic aromatic substitution processes involving displacement of fluorine atoms at activated sites ortho to ring nitrogen provide an indication of the synthetic possibilities offered using tetrafluoropyridazine as a starting material for the preparation of polysubstituted pyridazine and novel polyfunctional ring fused pyridazine systems with potential applications in the drug discovery arena.

Synthesis and biological activity of a new class of insecticides: the N-(5-aryl-1,3,4-thiadiazol-2-yl)amides.

Optimization studies on a high-throughput screening (HTS) hit led to the discovery of a series of N-(6-arylpyridazin-3-yl)amides with insecticidal activity. It was hypothesized that the isosteric replacement of the pyridazine ring with a 1,3,4-thiadiazole ring could lead to more potent biological activity and/or a broader sap-feeding pest spectrum. The resulting N-(5-aryl-1,3,4-thiadiazol-2-yl)amides were explored as a new class of insecticides. Several methods for 2-amino-1,3,4-thiadiazole synthesis were used for the preparation of key synthetic intermediates. Subsequent coupling to variously substituted carboxylic acid building blocks furnished the final targets, which were tested for insecticidal activity against susceptible strains of Aphis gossypii (Glover) (cotton aphid), Myzus persicae (Sulzer) (green peach aphid) and Bemisia tabaci (Gennadius) (sweetpotato whitefly). Structure-activity relationship (SAR) studies on both the amide tail and the aryl A-ring of novel N-(5-aryl-1,3,4-thiadiazol-2-yl)amides led to a new class of insecticidal molecules active against sap-feeding insect pests. © 2016 Society of Chemical Industry.