Pyridazinone Derivatives Research Articles

Pyridazinone hybrids: Design, synthesis and evaluation as potential anticonvulsant agents

A series of new hybrid benzothiazole containing pyridazinones derivatives were designed and synthesized fulfilling all the pharmacophoric requirements essential for the anticonvulsant activity. In-silico and in vitro studies revealed that some of these hybrid derivatives demonstrated admirable GABA AT inhibitory activity. An attempt has also been made to validate the results of in vitro GABA AT inhibition of the most potent compound SPS-5F (IC50 9.10 μM) through in vivo anticonvulsant screening. Compound SPS-5F administration significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme.

Effect of Aniline Concentrations on Fluorescence Intensities for a Newly Synthesized 3(2H)-Pyridazinone Derivative

Effect of Aniline Concentrations on Fluorescence Intensities for a Newly Synthesized 3(<i>2H</i>)-Pyridazinone Derivative

Design, Synthesis, and Pharmacological Screening of Pyridazinone Hybrids as Anticonvulsant Agents.

A series of new hybrid benzimidazole containing pyridazinones derivatives were designed and synthesized in accordance with the pharmacophoric requirements essential for the anticonvulsant activity. The synthesized compounds were evaluated for anticonvulsant activity on mice by the gold standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models. Among the compounds tested, SS-4F showed significant anticonvulsant activity in both the screens with ED50 values of 25.10 and 85.33 mg/kg in the MES and scPTZ screens, respectively. Compound SS-4F emerged as safer and effective anticonvulsant due to its several-fold higher protective indices. Further, the gamma-aminobutyric acid (GABA) estimation result showed a marked increase in the GABA level (1.7-fold) as compared to the control, which was further confirmed by good binding properties with the GABAA receptor.

SYNTHESIS, COMPUTER AIDED SCREENING AND PHARMACOLOGICAL EVALUATION OF 2/3-SUBSTITUTED-6(4-METHYLPHENYL)-4,5-DIHYDROPYRIDAZIN3(2H)-ONES, AND PYRIDAZINE SUBSTITUTED TRIAZINE

The present research work involved synthesis of some novel pyridazine derivatives and evaluation of their analgesic and anti-inflammatory activities in experimental animals to obtain safer non-steroidal anti-inflammatory drugs (NSAIDs). Friedal craft acylation reaction of succinic anhydride with toluene in the presence of anhydrous aluminum chloride gave 4-(4-methylphenyl)-4-oxo-butanoic acid ( 1) . The aryl propionic acid 1 on reaction with phenyl hydrazine and hydrazine hydrate yielded the pyridazinone derivative 2 and 3 , respectively. Reaction of the compound 3 with phosphorus oxychloride (POCl 3 ) produced the corresponding chloropyridazine derivative 4 . A 4-hydroxymethyl derivative of dihydropyridazinone ( 5) was synthesized by condensing 3 with methanol and formaldehyde (HCHO). The compound 5 on further treatment with guanidine hydrochloride in ethanol gave the pyridazino-triazine ( 6) . The synthesized compounds were investigated for their analgesic activity in mice and anti-inflammatory activity in Wistar albino rats. The molecular, pharmacokinetic and toxicity properties of the synthesized compounds were calculated by Molinspiration and Osiris property explorer software. The results of in-vivo anti-inflammatory studies revealed that the compound. 4 showed maximum inhibition in paw edema volume followed by compound no. 3 while the compound no. 4 exhibited excellent peripheral analgesic activity ( 74%) followed by the compound no. 5 . Compound no. 4 and 5 also showed good central analgesic effect increased the reaction time to 90 minutes. All the title compounds except compound 5 are predicted to be safe by Osiris online software and are likely to have good oral bioavailability as they obey Lipinski’s rule of five for drug likeness.

Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives.

Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule.

Rational Design of a Near‐Infrared Fluorescent Probe Based on a Pyridazinone Scaffold

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

Photophysical Properties of a Novel and Biologically Active 3(2H)-Pyridazinone Derivative Using Solvatochromic Approach.

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

Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors

Inhibition of cholinesterases is an effective method to curb Alzheimer’s disease, a progressive and fatal neurological disorder. A series of 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzalhidrazone) derivatives were designed, synthesized, and their inhibitory effects on acetylcholinesterase and butyrylcholinesterase were evaluated in pursuit of potent dual inhibitors. We obtained our compounds by the reaction of various substituted/nonsubstituted benzaldehydes with 6-[4-(3,4-dichlorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman’s method. 5f and 5i showed 75.52 and 71.72% acetylcholinesterase inhibition at 100 µg/ml, respectively. 5h and 5f, on the other hand, were the best butyrylcholinesterase inhibitors with 67.16 and 62.03% inhibition at the same concentration, respectively. 5f emerged as a potent dual cholinesterase inhibitor. Through molecular docking studies we predicted the inhibition mechanism of 5f for both enzymes in comparison with our previous derivatives, which differ in inhibition potency, and tried to get insights into the factors that affect receptor affinity in molecular level.

Analysis of Fluorescence Quenching for Newly Synthesized Biologically Active 3(2H)-pyridazinone Derivative by Aniline.

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

Solubility and thermodynamics of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in various neat solvents at different temperatures

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=293.2K to 313.2K” and “atmospheric pressure p=0.1MPa”. 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=313.2K” 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®.

Synthesis and Applications of Pyridazinones for Base oil Improvement

Three Pyridazinone derivatives of the type 4,5-dihydropyridazin-3(2H)-ones, N-(4-(6-oxo-5-((5-phenyl-1,3,4-thiadiazol-2-yl)amino)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) acetamide (4a), 6-(4-Chlorophenyl)-4-((5-phenyl-1,3,4-thiadiazol-2-yl)amino)-4,5-di-hydropyridazin-3(2H)-one (4b) and 6-(4-Bromophenyl)-4-((5-phenyl-1,3,4-thiadiazol-2-yl)amino)-4,5-dihydropyridazin-3(2H)-one (4c) were synthesized. They were characterized by the conventional tools of analysis, Elemental analysis, IR and 1H-NMR spectroscopy. The tools of analysis confirmed the structure of the three prepared compounds. These heterocyclic compounds are chemically stable and possess multi actions for base oil improvement. They are tested as antioxidants for local base oil through the change in total acid number (TAN). They gave good results as antioxidants base oil. Also these three synthesized compounds are tested as corrosion inhibitors for carbon steel in acid medium. The efficiency order for these tested compounds is ranked as follows: 4a > 4b > 4c. Energy of the highest occupied molecular orbital (EHOMO) and lowest unoccupied molecular orbital (ELUMO) for the three prepared compounds were calculated via the Ab initio method. Studying of the quantum chemical calculations of the synthesized compounds showed good matching with the experimental results.

Spectroscopic interactions of titanium dioxide nanoparticles with pharmacologically active 3(2H)-pyridazinone derivative

Herein, we report the spectroscopic interactions of titanium dioxide (TiO2) 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 TiO2 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 (ka) and quenching constant (KSV) 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 TiO2 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 TiO2 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.

Synthesis and biological screening of some chromonyl-substituted heterocycles derived from 2(3H)-furanone derivative

ABSTRACTA 2(3H)-furanone bearing chromonyl moiety at position-3 was synthesized and utilized for the construction of N-heterocycles such as pyrrolone, N-aminoquinolone, and pyridazinone derivatives. The reactivity of the chromonylfuranone toward some nitrogen nucleophiles such as ammonia, benzylamine, hydrazine, and phenylhydrazine was studied. On the other hand, thiation of the starting chromonylfuranone interestingly provides mono- and di-thiated products. The chemoselectivity of these reactions is discussed. The structures of all products obtained were elucidated from their analytical and spectral data. The antimicrobial activities of selected examples of the synthesized compounds were examined against two strains of bacteria and two fungus strains. Some of them showed promising antimicrobial activities.

Solubility and thermodynamic/solvation behavior of 6-phenyl-4,5-dihydropyridazin-3(2H)-one in different (Transcutol + water) mixtures

Abstract Pyridazinone derivatives are useful cardiovascular drugs which suffer from weak aqueous solubility and toxicity problems. Hence, in this work, the solubility of pyridazinone derivative i.e. 6-phenyl-4,5-dihydropyridazin-3(2H)-one (PDP-6) was measured in various “2-(2-ethoxyethoxy)ethanol (Transcutol®) + water” mixtures at temperatures “T = 293.2 K to 313.2 K and pressure “p = 0.1 MPa”. The experimental solubilities of PDP-6 were correlated with “Apelblat, Van't Hoff and Yalkowsky models” in terms of mean percent deviations and coefficient of determination. The highest solubilities of PDP-6 as mole fraction were obtained in pure Transcutol (5.27 × 10− 1 at T = 313.2 K). However, the lowest one was obtained in pure water (7.45 × 10− 7 at T = 293.2 K). “Apparent thermodynamic analysis” of solubilities of PDP-6 as mole fraction indicated an “endothermic dissolution” of PDP-6 in all “Transcutol + water” mixtures due to its positive values. “Enthalpy-entropy compensation” analysis indicated that the solvation of PDP-6 was “enthalpy-driven” in all “Transcutol + water” mixtures evaluated. Based on the results of the current study, PDP-6 has been proposed as practically insoluble in water and very soluble in Transcutol at T = 298.2 K.

Optimization and Synthesis of Pyridazinone Derivatives as Novel Inhibitors of Hepatitis B Virus by Inducing Genome-free Capsid Formation.

The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50 = 0.087 ± 0.002 μM), low cytotoxicity (CC50 = 90.6 ± 2.06 μM), sensitivity to nucleoside analogue-resistant HBV mutants, and synergistic effect with nucleoside analogues in HepG2.2.15 cells.

Pyridazinone: an attractive lead for anti-inflammatory and analgesic drug discovery.

In spite of the availability of a large number of anti-inflammatory and analgesic agents, fighting pain and inflammation remains a common problem. The current review article discusses the need of novel therapeutic targets for risk-free anti-inflammatory and analgesic therapy and summarizes some new agents in various stages of drug discovery pipeline. Pyridazin-3(2H)-ones are nitrogen-rich heterocyclic compounds of considerable medicinal interest due to their diverse biological activities. The current review article focuses on progressive development of this attractive scaffold for the design and synthesis of new pyridazinone-based anti-inflammatory and analgesic agents. Mechanistic insights into the anti-inflammatory and analgesic properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described.

Some Conventional and Convenient Process for Functionalization of 6-Phenyl-4,5-Dihydropyridazinone Compounds

The pyridazinone derivatives, particularly those bearing substituted different group or atom at a different position, have attracted considerable attention due to their characteristic pharmacological and other anticipated activities. These activities promoted the synthesis of a large number of substituted pyridazinone derivatives in order to explore the usefulness of this heterocyclic system. In the present review, various synthetic methods have been studied for the synthesis of substituted pyridazinone derivatives. The behaviour of the pyridazinone toward formaldehyde/piperidine, ethyl chloroacetate, chloroacetic acid, benzene sulfonyl chloride, bromine/acetic acid and aromatic aldehydes has also been studied. However, the reactions of the chloro derivative resulting from the reaction of pyridazinone with phosphorus oxychloride (POCl&lt;sub&gt;3&lt;/sub&gt;). The behavior of chloropyridazine toward hydrazines, thiourea, sodium azide, anthranilic acid, aromatic amines and sulfa compounds have also been taken into consideration. Thethiopyridazinone derivativeswere prepared from the reaction of pyridazinone with phosphorus pentasulphide (P&lt;sub&gt;2&lt;/sub&gt;S&lt;sub&gt;5&lt;/sub&gt;). All the structures of were established on the based of spectroscopic data.&lt;p&gt; &lt;/p&gt;&lt;p&gt;&lt;strong&gt; &lt;/strong&gt;&lt;/p&gt;

Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships.

Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.

ChemInform Abstract: The Therapeutic Journey of Pyridazinone

AbstractReview: 190 refs.

6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone - An important chemical moiety for development of cardioactive agents: A review

6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone moiety is a vital structural part of many cardio-active pyridazinone derivatives which are either in clinical use or have been tested in clinical trials. These include imazodan, CI-930, pimobendan, indolidan, levosimendan, SK&F-93741, Y-590, meribendan, NSP-804, NSP-805, bemoradan, senazodan, amipizone, prinoxodan, SKF 95654, siguazodan and KF 15232. This article briefly reviews relevant literature on various reports on the synthesis and use of this moiety for development of cardio-active agents. Keywords : 6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, Cardio-active agents, Imazodan, Pimobendan, Indolidan, Levosimendan