Synthesis and biological activity of 2-sulfonarylhydrazinylidene 1,3-diketones and their pyrazole derivatives

Khudina, O. G.; Elkina, Natalia А.; Burgart, Ya. V.; Ежикова, М. А.; Кодесс, М. И.; Esaulkova, Ya. L.; Zarubaev, V. V.; Shtro, A. A.; Триандафилова, Галина А.; Красных, О. П.; Malysheva, K. O.; Герасимова, Н. А.; Евстигнеева, Н. П.; Салоутин, В. И.

doi:10.1007/s11172-022-3696-7

Cited by 11 publications

(7 citation statements)

References 33 publications

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“…Chemistry 1-Phenyl-3-trifluoromethylpyrazol-5-ol 1 a was chosen as the main starting block for modification, which itself showed a pronounced analgesic effect in vivo in the hot plate test, but with moderate acute toxicity. [32] The introduction of the methoxy function instead of the hydroxyl group led to an increase in the analgesic effect and a decrease in the toxic properties of the methoxy derivative 2 a. To compare the biological properties of the resulting alkoxy derivatives, 1-aryl-3-trifluoromethylpyrazol-5-ols 1 b,c,f, pentafluoroethyl and methyl analogues 1 d,e,g were also used as initial reagents.…”

Section: Resultsmentioning

confidence: 99%

“…1‐Phenyl‐3‐trifluoromethylpyrazol‐5‐ol 1 a was chosen as the main starting block for modification, which itself showed a pronounced analgesic effect in vivo in the hot plate test, but with moderate acute toxicity [32] . The introduction of the methoxy function instead of the hydroxyl group led to an increase in the analgesic effect and a decrease in the toxic properties of the methoxy derivative 2 a .…”

Section: Resultsmentioning

confidence: 99%

“…[25] We are also actively carrying out research on the development of analgesics based on fluorine-containing pyrazoles. [26][27][28][29][30][31][32] Recently, we have synthesized polyfluoroalkylcontaining MeN-and MeO-derivatives of pyrazol-5-ols as analogues of antipyrine and celecoxib, [33] which revealed the pronounced analgesic activity in the hot plate test. Among the obtained derivatives, 5-methoxy-3-(trifluoromethyl)-1phenylpyrazole was distinguished by a combination of high analgesic activity in the in vivo hot plate test with low acute toxicity, which is a very important point for the development of new analgesics.…”

Section: Introductionmentioning

confidence: 99%

“…We are also actively carrying out research on the development of analgesics based on fluorine‐containing pyrazoles [26–32] . Recently, we have synthesized polyfluoroalkyl‐containing MeN‐ and MeO‐derivatives of pyrazol‐5‐ols as analogues of antipyrine and celecoxib, [33] which revealed the pronounced analgesic activity in the hot plate test.…”

Section: Introductionmentioning

confidence: 99%

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5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

et al. 2023

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Chemoselective O‐alkylation of 1‐aryl‐3‐polyfluoroalkylpyrazol‐5‐oles under basic conditions resulted in a series of 5‐alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug‐like. In experiments in vivo (CD‐1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds – >600 mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28–104 % at 1 h and 37–109 % at 2 h after administration) in vivo in the hot plate test (SD rats, 15 mg/kg, intraperitoneal (ip)). The lead compound was 4‐([1‐phenyl‐3‐(trifluoromethyl)pyrazol‐5‐yl]oxy)butan‐1‐ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin‐induced nociception (CD‐1 mice, 15 mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in in vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5‐Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in in vivo tests.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

et al. 2023

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“…The 19 F NMR spectrum of compound 5 has a chemical shift of the CF 3 group at δ 100.77 ppm, which corresponds to the 5-CF 3isomer, and a similar signal for 3-CF 3 -aminopyrazole 6 is observed at δ 104.48 ppm. [30,42] The 13 C NMR spectra of aminopyrazoles 5, 6 are characterized by the presence of quartet signals of carbon atoms of the CÀ CF 3 group at δ 116.32 and 129.14 ppm, respectively. The change of the alkylation direction with butyl bromide in comparison with methylation can be explained by HSAB theory, [43][44][45] According to XRD data, compound 7 a is 1-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3-phenylthiourea (Figure 3).…”

Section: Chemistrymentioning

confidence: 99%

Modifications of 4‐Amino‐substituted 5‐Phenyl‐3‐(trifluoromethyl)pyrazoles for the Development of New Analgesics

Shchegolkov,

Perminova,

Malkova

et al. 2023

ChemistrySelect

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To develop the new analgesics, different approaches to the modification of 4‐amino‐5‐phenyl‐3‐(trifluoromethyl)pyrazoles were proposed. A series of 4‐(het)arylimino‐3‐(trifluoromethyl)‐5‐phenylpyrazoles, existing as the E‐isomer, was synthesized by condensation of the 4‐aminopyrazoles with various aldehydes. Methylation of the initial substrates occurred at the NH2 group, while alkylation with bromobutyl was successfully carried out only for NH‐pyrazole to yield 3‐ and 5‐CF3‐isomeric N‐butyl‐substituted pyrazoles. The addition of phenylisothiocyanate to 4‐aminopyrazoles allowed us to introduce a thiourea fragment into their structure. According to computer calculations, all derivatives of aminopyrazoles have an acceptable ADME profile. Using the “hot plate” test in vivo, the analgesic activity of a number of the synthesized compounds was evaluated. Introducing the phenylmethanimine fragment allows us to obtain 1‐phenyl‐N‐(5‐phenyl‐3‐(trifluoromethyl)pyrazol‐4‐yl)methan‐imine as the lead compound with the analgesic activity in 1.4–2.2 times more than effect of the initial 4‐aminopyrazole, diclofenac and metamizole. In addition, the lead compound had low acute toxicity.

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Regioselective synthesis of 2-aryl-5-(polyfluoroalkyl)pyridazin-3-ones based on 2-arylhydrazinylidene 1,3-dicarbonyl compounds

et al. 2023

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Synthesis and biological activity of 2-sulfonarylhydrazinylidene 1,3-diketones and their pyrazole derivatives

Cited by 11 publications

References 33 publications

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

5‐Alkoxy‐1‐aryl‐3‐polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels

Modifications of 4‐Amino‐substituted 5‐Phenyl‐3‐(trifluoromethyl)pyrazoles for the Development of New Analgesics

Regioselective synthesis of 2-aryl-5-(polyfluoroalkyl)pyridazin-3-ones based on 2-arylhydrazinylidene 1,3-dicarbonyl compounds

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