3-Methoxypyrazoles from 1,1-dimethoxyethene, few original results

Salanouve, Elise; Guillou, Sandrine; Bizouarne, Marine; Bonhomme, Frédéric; Janin, Yves L.

doi:10.1016/j.tet.2012.02.057

Cited by 17 publications

(9 citation statements)

References 27 publications

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“…In conclusion, along with our previous report, this study made good use of the alkoxypyrazole chemistry we previously reported, − which somehow cleared a sort of “chemical blind spot” existing in pyrazole chemistry. The ensuing screenings of the resulting new chemical entities led us to extensively explore the structure–activity relationship of a new series of human DHODH inhibitors.…”

Section: Discussionsupporting

confidence: 71%

“…As explained in more detail in our previous report, in the course of a screening campaign of new chemical entities − against infectious agents, compounds 1 and 2 were found active on our whole cell measles virus replication assay (Figure ) . An initial structure–activity study led to confirmation of the potential of this original chemotype and to greatly improved antiviral compounds, including the 2-(3-isopropyloxy-1 H -pyrazol-1-yl)pyrimidine derivative 3 , which displayed a subnanomolar MIC 50 on this measles virus replication assay (Figure ).…”

Section: Introductionsupporting

confidence: 53%

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Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

et al. 2015

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Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure–activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionsupporting

confidence: 53%

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

et al. 2015

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“…Among many libraries, close to 800 new chemical entities featuring a pyrazole nucleus were thus assayed. Concerning the structural originality of the N-arylated 3-ethoxypyrazoles included in this library, it is based on the fact that the vast majority of N -arylpyrazoles have been made using the Knorr condensation between β-ketoesters and arylhydrazines which leads to 5-hydroxy- N -arylpyrazoles. , The preparation of the far less described isomeric N-arylated 3-alkoxypyrazoles or 3-hydroxypyrazoles led us to report on few original aspects of 3/5-alkoxypyrazoles chemistry, which indeed provided synthetic paths to new chemical entities. − Luckily, the 3-alkoxypyrazoles 1 and 2 depicted in Figure turned out to be active on the antiviral assays described above. Since these fairly original compounds had no significant cellular toxicity at their antiviral concentration, they became the starting points of an iterative process of synthesis and evaluation which, as described in this report, led to 2-(3-alkoxy-1 H -pyrazol-1-yl)pyrimidine derivatives endowed with nanomolar level of antiviral effect.…”

Section: Introductionmentioning

confidence: 99%

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)pyrimidine Derivatives as Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

et al. 2015

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From a research program aimed at the design of new chemical entities followed by extensive screening on various models of infectious diseases, an original series of 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidines endowed with notable antiviral properties were found. Using a whole cell measles virus replication assay, we describe here some aspects of the iterative process that, from 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)pyrimidine, led to 2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-5-ethylpyrimidine and a 4000-fold improvement of antiviral activity with a subnanomolar level of inhibition. Moreover, recent precedents in the literature describing antiviral derivatives acting at the level of the de novo pyrimidine biosynthetic pathway led us to determine that the mode of action of this series is based on the inhibition of the cellular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this pathway. Biochemical studies with recombinant human DHODH led us to measure IC50 as low as 13 nM for the best example of this original series when using 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone (coenzyme Q1) as a surrogate for coenzyme Q10, the cofactor of this enzyme.

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“…Good results in the iodination of pyrazoles with donor substituents were obtained using the I 2 –NaI–K 2 CO 3 system (yields 75–90% at 20–25 °C in aq. EtOH) [ 62 , 63 , 64 ]. A solution of N-iodosuccinimide in acidic media (50% aq.…”

Section: Electrooxidative C–h Halogenation Of Pyrazole and Its Substituted Derivativesmentioning

confidence: 99%

Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds

et al. 2021

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The review summarizes for the first time the poorly studied electrooxidative functionalization of pyrazole derivatives leading to the C–Cl, C–Br, C–I, C–S and N–N coupling products with applied properties. The introduction discusses some aspects of aromatic hydrogen substitution. Further, we mainly consider our works on effective synthesis of the corresponding halogeno, thiocyanato and azo compounds using cheap, affordable and environmentally promising electric currents.

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3-Methoxypyrazoles from 1,1-dimethoxyethene, few original results

Cited by 17 publications

References 27 publications

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

Original 2-(3-Alkoxy-1H-pyrazol-1-yl)pyrimidine Derivatives as Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds

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