2166-31-6Relevant academic research and scientific papers
Synthesis, Characterization and Solubility Determination of 6-Phenyl-pyridazin-3(2H)-one in Different Pharmaceutical Solvents
Shakeel, Faiyaz,Imran, Mohd,Haq, Nazrul,Alshehri, Sultan,Khalid Anwer
, (2019)
The current research work proposed the solubility data and solution thermodynamic properties of the cardiovascular agent 6-phenylpyridazin-3(2H)-one [PPD] in twelve pharmaceutical solvents at “T = 298.2 K to 318.2 K” and “p = 0.1 MPa”. The measured solubilities of PPD were regressed well with “van’t Hoff and Apelblat models”. The solid phases of pure and equilibrated PPD were characterized using differential scanning calorimetry and powder X-ray differactometry, and the results suggested no transformation of PPD into solvates/hydrates/polymorphs after equilibrium. The solubilities of PPD in a mole fraction at “T = 318.2 K” were noted at a maximum in dimethyl sulfoxide (DMSO, 4.73 × 10?1), followed by polyethylene glycol-400 (PEG-400, 4.12 × 10?1), Transcutol (3.46 × 10?1), ethyl acetate (EA, 81 × 10?2), 2-butanol (2.18 × 10?2), 1-butanol (2.11 × 10?2), propylene glycol (PG, 1.50 × 10?2), isopropyl alcohol (IPA, 1.44 × 10?2), ethylene glycol (EG, 1.27 × 10?2), ethanol (8.22 × 10?3), methanol (5.18 × 10?3) and water (1.26 × 10?5). Similar tendencies were also noted at other studied temperatures. The results of the “apparent thermodynamic analysis” showed an endothermic and entropy-driven dissolution of PPD in all pharmaceutical solvents. The results of the activity coefficients suggested a maximum interaction at the molecular level in PPD-DMSO, PPD-PEG-400 and PPD-Transcutol, compared with other combination of the solute and solvents.
Discovery of novel pyridazine-based cyclooxygenase-2 inhibitors with a promising gastric safety profile
Afroz Bakht, Md.,Diwan, Anupama,Imran, Mohd,Khan, Abida,Thabet, Hamdy Kh.
, (2020)
Cyclooxygenase-2 (COX-2) is implicated in the development of chronic inflammatory diseases. Recently, pyridazine derivatives have emerged as a novel prototype to develop COX-2 inhibitors. Accordingly, some pyridazine-based COX-2 inhibitors are reported herein. The reaction of aldehyde 3 and different hydrazines yielded the corresponding hydrazones. The hydrazones were further derivatized to the title compounds, which were assessed for COX-1 and COX-2 inhibitory action, gastric ulcerogenic effects, and lipid peroxidation properties. Molecular docking studies and determination of the physicochemical parameters were also carried out. The allocated structures of the reported compounds were coherent with their spectroscopic data. The compounds 9a (IC50 = 15.50 nM, 114.77%), 9b (IC50 = 17.50 nM, 101.65%), 12 (IC50 = 17.10 nM, 104.03%), 16b (IC50 = 16.90 nM, 105.26%), and 17 (IC50 = 17.70 nM, 100.5%) displayed better COX-2 inhibition than celecoxib (IC50 = 17.79 nM, 100%). These outcomes were harmonious with the molecular docking studies of 9a, 9b, 12, 16b, and 17. These compounds also displayed comparable onset and the duration of action concerning celecoxib and indomethacin in the in vivo studies. No ulcerogenic effects were observed for 9a and 12, whereas 9b, 16b, and 17 showed an insignificant ulcerogenic effect compared to celecoxib. The compounds 9a, 9b, 12, 16b, and 17 displayed a better lipid peroxidation profile than celecoxib and indomethacin. The compounds 9a (%ABS = 84.09), 9b (%ABS = 84.09), 12 (%ABS = 66.87), 16b (%ABS = 75.02), and 17 (%ABS = 81.42) also displayed appreciable calculated absorption compared to celecoxib (%ABS = 82.09). The compounds 9a, 9b, 11, 16b, and 17 have been recognized and postulated as non-ulcerogenic COX-2 inhibitors with promising physicochemical parameters and gastric safety profile. These compounds may be useful candidates to combat diseases caused by higher levels of COX-2.
Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies
Ahmed, Marwa F.,Santali, Eman Y.,Mohi El-Deen, Eman M.,Naguib, Ibrahim A.,El-Haggar, Radwan
, (2020/11/27)
Novel hybrids of pyridazine-pyrazoline were synthesized aiming to develop new antiproliferative candidates. All compounds were submitted to the National Cancer Institute (NCI), USA, and many were proved to have significant antiproliferative activity. In addition, in vitro studies of the epidermal growth factor receptor (EGFR) inhibition showed that compounds IXn, IXg, IXb and IXl exhibited excellent inhibitory effect (IC50 = 0.65, 0.75, 0.82 and 0.84 μM, respectively) compared to Erlotinib (IC50 = 0.95 μM). The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compounds IXg and IXn due to their significant EGFR inhibition. Flow cytometeric analysis indicated that compounds IXg and IXn result in increased cell numbers in phase G2/M, suggesting cell cycle arrest in phase G2/M in UO-31cells. Furthermore, real time PCR assay illustrated that compounds IXg and IXn elevated Bax/Bcl2 ratio which confirmed the mechanistic pathway of them. Moreover, the apoptotic induction of UO-31 renal cancer cells was enhanced effectively through activation of caspase-3 by compounds IXg and IXn. On the other hand, molecular docking study was performed to investigate binding mode of interaction of compounds with EGFR-PK in the active site with the aim of rationalizing its promising inhibitory activity. Finally, based on the aforementioned findings, compounds IXg and IXn could be considered as effective apoptosis modulators and promising leads for future development of new anti-renal cancer agents.
Copper-mediated rapid and facile oxidative dehydrogenation of dihydrobenzocarbazoles
Humne, Vivek T.,Ulhe, Avinash G.
supporting information, (2020/03/16)
Rapid method for the oxidative dehydrogenation of dihydrobenzocarbazoles has been introduced by using bench scale and commercially available reagent; copper chloride, in excellent yield with easy workup. The scope of the reaction has been studied with broad range of substitutes.
Synthesis of novel N-substitutedphenyl-6-oxo-3-phenylpyridazine derivatives as cyclooxygenase-2 inhibitors
Khan, Abida,Diwan, Anupama,Thabet, Hamdy K,Imran, Mohd
, p. 573 - 584 (2020/03/23)
Some novel non-ulcerogenic N-substitutedphenyl-6-oxo-3-phenylpyridazines as COX-2 inhibitors have been developed (Supplementary material Appendix 1). The novel aldehyde 3 was prepared by reacting 6-phenylpyridazin-3(2H)-one with 4-fluorobenzaldehyde. The aldehyde 3 was reacted with different hydrazines and thiazolidin-4-ones to obtain the novel N-substitutedphenyl-6-oxo-3-phenylpyridazine derivatives. These were assessed for their anti-inflammatory potential and gastric ulcerogenic effects. The molecular docking investigations were also undertaken. The spectroscopic data were coherent with the allocated structures of the compounds. The compounds 4a (IC50 = 17.45 nm; p 50 = 17.40 nm; p 50 = 16.76 nm; p 50 = 17.15 nm; p 50 = 17.79 nm; p .05). These findings were consistent with the molecular docking investigations of 4a, 4b, 5a, and 10. The in vivo anti-inflammatory profile of 4a, 4b, 5a, and 10 was also superior to celecoxib and indomethacin. The compounds 4b, 5a, and 10 revealed no gastric ulcerogenic effects, wherein the compound 4a produced almost negligible gastric ulcerogenic effects than celecoxib and indomethacin. The compounds 4a, 4b, 5a, and 10 have been postulated as promising non-ulcerogenic COX-2 inhibitors.
Rhodium(III)-Catalyzed Alkynylation of 4-Arylphthalazin-1(2H)-one Scaffolds via C-H Bond Activation
Du, Xuxin,Hou, Hongcen,Zhao, Yongli,Sheng, Shouri,Chen, Junmin
supporting information, p. 1100 - 1107 (2020/02/25)
Selective C–H bond alkynylation toward modular access to material and pharmaceutical molecules is of great desire in modern organic synthesis. Disclosed herein is rhodium(III)-catalyzed selective C–H bond mono-/bialkynylation of 4-aryl phthalazin-1(2H)-one was developed. The silver salt AgSbF6 are demonstrated to play a vital role in promoting the bialkynylation reactions. The present alkynylation strategy is simple, efficient, and features high functional group tolerance and broad substrate scope under an air atmosphere. Additionally, 6-aryl pyridazin-3(2H)-one scaffold is amenable to the selective monoalkynylation and sequential bialkynylation, respectively.
Scope and limitation of propylene carbonate as a sustainable solvent in the Suzuki-Miyaura reaction
Czompa, Andrea,Pásztor, Balázs László,Sahar, Jennifer Alizadeh,Mucsi, Zoltán,Bogdán, Dóra,Ludányi, Krisztina,Varga, Zoltán,Mándity, István M.
, p. 37818 - 37824 (2019/12/03)
The Suzuki-Miyaura reaction is one of the most used transformations in drug research. Thus making this reaction more sustainable is of considerable current interest. Here we show that propylene carbonate (PC) can be used as a solvent for the Suzuki-Miyaura reaction. PC is one of the greenest solvents since it is synthesized under green conditions by the use of carbon dioxide in the air. All reactions proceeded well and good or excellent yields were observed for the biaryl products. Nonetheless in the case of pyridazinones, 2-hydroxypropyl- chain containing side-products were observed. Importantly, this fact allowed the isolation of several novel compounds which were generated under prominently green conditions.
Design and synthesis of 3-aminophthalazine derivatives and structural analogues as PDE5 inhibitors: anti-allodynic effect against neuropathic pain in a mouse model
Bollenbach, Maud,Lugnier, Claire,Kremer, Mélanie,Salvat, Eric,Megat, Salim,Bihel, Frédéric,Bourguignon, Jean-Jacques,Barrot, Michel,Schmitt, Martine
supporting information, p. 269 - 290 (2019/06/05)
Neuropathic pain is a chronic pain caused by a lesion or disease affecting the somatosensory nervous system. To date, no specific treatment has been developed to cure this pain. Antidepressants and anticonvulsant drugs are used, but they do not demonstrate universal efficacy, and they often cause detrimental adverse effects. Some studies highlighted the efficacy of sildenafil, a well-known inhibitor of phosphodiesterase 5 (PDE5, (IC50 = 3.3 nM)), in models of pain. Based on these results, we focused our attention on MY 5445, another known PDE5 inhibitor. Homologues, isosteres and structural analogues of MY 5445 were designed and all synthesized compounds were evaluated for their inhibitory activity toward PDE5. Selectivity profiles towards other PDE1-4 isoenzymes, water solubility and stability in acidic medium of the most potent PDE5 inhibitors were determined and the aminophthalazine 16h and its mimetic 41n (3-aminoindazole)were evaluated in comparison to MY 5445 (4b)in vivo in a model of neuropathic pain induced by sciatic nerve cuffing in mice (3 and 0.5 mg/kg, ip twice a day). Both compounds showed the same efficacy on neuropathic allodynia as MY 5445, and thus produced a significant relief of mechanical hypersensitivity after 12 days of treatment.
AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN DEGRADATION
-
Page/Page column 297-298, (2017/12/01)
This invention provides amine-linked C3-glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.
Synthesis, vasorelaxant activity and 2D-QSAR study of some novel pyridazine derivatives
George, Riham F.,Saleh, Dalia O.
, p. 663 - 673 (2016/01/09)
Novel 3,6-disubstituted pyridazines were synthesized by facile method and screened for their vasorelaxant properties utilizing isolated thoracic rat aortic rings. Compounds 8a and 11a exerted potent vasorelaxant activity (IC50 = 198 and 177 μM, respectively) relative to doxazosin mesylate (used reference standard, IC50 = 226 μM), that, they may represent promising hits for treatment of cardiovascular disorders. The observed activity was validated by a statistically significant QSAR model (N = 32, n = 6, R2 = 0.811782, R2cvOO = 0.7153, R2cvMO = 0.7209, F = 17.9708, s2 = 9.65226 × 10-8) that was obtained employing CODESSA-Pro software.
