Pyrazole Moiety Research Articles

Iridium-Catalyzed C–H Activation and Deuteration of Primary Sulfonamides: An Experimental and Computational Study

Iridium-catalyzed C–H activation and ortho-hydrogen isotope exchange is an important technology for allowing access to labeled organic substrates and aromatic drug molecules and for the development of further C–H activation processes in organic synthesis. The use of [(COD)Ir(NHC)Cl] complexes (NHC = N-heterocyclic carbene) in the ortho-deuteration of primary sulfonamides under ambient conditions is reported. This methodology has been applied to the deuteration of a series of substrates, including the COX-2 inhibitors Celecoxib and Mavacoxib, demonstrating selective complexation of the primary sulfonamide over a competing pyrazole moiety. The observed chemoselectivity can be reversed by employing more encumbered catalyst derivatives of the type [(COD)Ir(NHC)(PPh3)]PF6. Computational studies have revealed that, although C–H activation is rate-determining, substrate complexation or subsequent C–H activation can be product-determining depending on the catalyst employed.

Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand

We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a–h) or a thiazole moiety (compounds 4a–e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki=0.25nM, cellular EC50 of 194nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site.

ChemInform Abstract: Ruthenium‐Catalyzed C—H Silylation of 1‐Arylpyrazole Derivatives and Fluoride‐Mediated Carboxylation: Use of Two Nitrogen Atoms of the Pyrazole Group.

AbstractThe two nitrogen atoms play a crucial role for the ortho‐directing effect of the pyrazole moiety in the formation of the intermediately generated silylated 1‐arylpyrazole derivatives.

Synthesis of 4-aryl-3-[2-hydroxy-4-(2-cytisin-12-ylethoxy)phenyl]pyrazoles

Recyclization of N 12-cytisinylethoxy derivatives of natural isoflavonoids and their analogs through the action of hydrazine hydrate was studied. A series of substituted 3-(2-hydroxyphenyl)-4-arylpyrazoles containing cytisine and pyrazole moieties were synthesized.

Morphology and Emission Tuning in Fluorescent Nanoparticles Based on Phenylenediacetonitrile

Organic nanoparticles exhibiting tunable emission properties in response to morphology changes are attractive for application in low-cost fluorescence sensors, e.g., for sensing vapors, temperature, etc., and therefore, convenient ways for altering nanoparticle morphology are highly desired. In this work, phenylenediacetonitrile-based molecules featuring aggregation-induced emission enhancement which are suitable for the realization of morphology-tunable nanoparticles by precipitation method have been designed. The morphology tuning was enabled by rational functionalization of the molecular backbone with pyrazole moieties and adjacent alkoxy/cyclic side-groups, which were varied in size and branchiness. The longer alkoxy chains generally caused formation of crystalline nanostructures, while shorter ones resulted in preferably amorphous nanoaggregates. Remarkably, the sharp tuning of the nanoparticle morphology (crystalline → amorphous → crystalline) with the subsequent high-contrast emission switching (emissive → nonemissive → emissive) was achieved for phenylenediacetonitrile bearing dihexylmethoxy-type side-groups by adjusting solvent/nonsolvent ratio (1/1 → 1/4 → 1/9) in the mixture with the dissolved compound. Electron and polarized optical microscopy data confirmed the intermediate nonemissive state (ΦF = 2%) emanates from amorphous spherical aggregates, whereas two highly emissive states (ΦF up to 70%) originate from nanowire-like crystalline particles, which were attributed to different phenylenediacetonitrile polymorphs. Finally, the applicability of the phenylenediacetonitrile-based fluorescent nanoparticles for organic vapor sensing was demonstrated.

Novel pyrazole–pyrazoline hybrids endowed with thioamide as antimalarial agents: their synthesis and 3D-QSAR studies

One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ-sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC50 of 1.13 µM. The in vitro results were further validated by quantitative structure–activity relationship (QSAR).

Synthesis, antibacterial evaluation, and SAR study of some novel 3-aryl/heteroaryl-9-methyl-1,2,4-triazolo-[4,3-a]-quinoline derivatives

A series of new quinolin-2-yl moiety linked hydrazones of various aryl/heteroaryl aldehydes has been prepared which on treatment with iodobenzene diacetate in dichloromethane yielded novel triazolo[4,3-a]quinoline derivatives. All the synthesized compounds were characterized on the basis of their FT-IR, 1H, 13C NMR, and mass spectral data. Compounds thus obtained were tested in vitro for their antibacterial activity against three Gram-positive bacterial, namely Enterococcus, Bacillus subtilis, and Staphylococcus aureus, and three Gram-negative bacterial strains, namely Psuedomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae using agar well diffusion method. The percentage similarity of all compounds was also assessed on the basis of physico-chemical and steric parameters as compared to a standard drug, Cefixime using Chem 3D software. Most of the compounds possessed good percentage similarity and exhibited admirable antibacterial activity when compared with the standard drug. Compounds (4a, 4b, 3a, 3c, and 3d) containing pyrazole moiety were found to be most effective against Gram-positive bacteria, S. aureus and B. subtilis.

A Synthesis of Novel Pyrazolylthienopyrimidine Derivatives as IL-6/STAT3 Inhibitors

The interleukin-6 (IL-6) as a pro-inflammatory cytokine with TNF-α and IL-8 plays a central role in the induction of inflammation as well as in the continuation of a chronic inflammatory immune response. And, an over-production of IL-6 have been found in inflammatory tissues of several diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, osteoarthritis, multiple myeloma, and also in human atherosclerotic plaque. IL-6 binds to its receptor (IL-6R, a ligand-binding 80 kDa glycoprotein chain) and induces the homodimerization of a signal transducing glycoprotein 130 (gp130), leading to the activation of the Janus kinase (Jak)/signal transducer and signal activator of transcription-3 (STAT3). STAT3 is also frequently overexpressed or persistently activated in most tumors and cancer, and activated STAT3 was found to suppress tumorimmune surveillance. Therefore, the blockade of STAT3 activation pathway stimulated by IL-6 could be an attractive therapeutic target for discovery of new drugs and is currently under intense investigation. In the other hand, thienopyrimidine and their derivatives are an important class of the most biologically active compounds, having diverse activities such as antibacterial, analgesic, antitumor, antioxidant, P2Y12 platelet aggregation inhibitor, and Aurora kinase inhibitor. We have synthesized over the years thienopyrimidine derivatives of promising biological activity. As part of a programme to discover novel inhibitors using thienopyrimidines, some of these compounds were found to possess potent IL-6/STAT3 inhibition. This result encouraged us to prepare new thienopyrimidines having pyrazole moiety in attempt to improve the IL-6/STAT3 inhibitory activity. Pyrazoles have been also reported to have a wide range of biological properties. Moreover, incorporation of pyrazole moiety into other heterocycles gave various pharmacological activities. Although a lot of methodologies have been developed over the years, the regiocontrolled and practical synthesis of 1,5-pyrazoles over 1,3-pyrazole is still less literature precedent and remains a noteworthy challenge. To the best of our knowledge no report have so far made in the synthesis of regioselective pyrazolylthienopyrimidine by the one pot reaction of (E)-3-(dimethylamino)-1-phenylprop-2en-1-one 2 with 4-hydrazinothienopyrimidine 1. Herein we report the efficient synthesis and biological activity of novel pyrazolylthienopyrimidine derivatives, 3A and 3B, as IL-6/ STAT3 inhibitor. The required reactant 2 can be easily prepared by the reaction of acetophenone with N,N-dimethylformamide dimethyl acetal (DMFDMA) in refluxing xylene. The reactants, 1A and 1B, were also obtained according to the procedure we have previously reported. In our initial studies toward synthesis of substituted pyrazolylthienopyrimidine, (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2a) was reacted with 4-hydrazinothieno[2,3-d]pyrimidine (1A) in THF at reflux for 10 h. It was found that three products from the reaction mixture were formed, respectively, 4-(5-phenyl1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Aa, 1,5-isomer, 35%), 4-(3-phenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (4Aa, 1,3-isomer, 20%) and 1,2-adduct (5Aa, 15%), as shown Table 1. Accordingly, reaction optimization for the regioselective formation of 1,5-isomer was investigated at the various conditions (catalyst, reaction temperature and solvent). When the same reaction was carried out in refluxing ethanol in the presence of 1 equiv HCl as a catalyst, 3Aa was obtained as a major product in optimum yield (65%, Table 1, entry 6) within 6 h. Next, as depicted in Table 2, the reaction of 1A with 2b-h Table 1. Optimization for the reaction of 1A with 2a

Synthesis, characterization, and pharmacological evaluation of some novel thiadiazoles and thiazoles incorporating pyrazole moiety as anticancer agents

Two series of novel 2-[[1-(5-methyl-1-phenyl-5-substituted-1H-pyrazol-4-yl)ethylidene]hydrazono]-3-phenyl-2,3-dihydro-1,3,4-thiadiazole derivatives and 2-[5-(4-chlorophenyl)-5′-methyl-1′-phenyl-3,4-dihydro-1′H,2H-[3,4′-bipyrazol]-2-yl]-4-substituted-5-(phenyldiazenyl)thiazole derivatives were prepared from reaction of hydrazonoyl halides with methyl 2-[1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethylidene]hydrazine-carbodithioate and thiosemicarbazide derivative, respectively. The newly synthesized derivatives were elucidated by elemental analysis, spectral data, and alternative synthetic routes, whenever possible. The anti-cancer activity of the selected products against the breast carcinoma cell line MCF-7 was determined by WST-1 assay indicating concentration-dependent cellular growth inhibitory effect especially for three compounds with dose response curves indicating IC 50 values of 21.3 ± 0.72, 21.3 ± 0.72, and 23.56 ± 0.81 µg cm−3, respectively. Confocal laser scanning imaging of the treated cells stained by rhodamin 123 and acridine orange dyes confirms that the selected compounds inhibit the mitochondrial lactate dehydrogenase enzymes. The obtained results revealed promising anticancer activity.

Synthesis and biological activity of some novel β-diketones containing pyrazole moiety

Synthesis and biological activity of some novel β-diketones containing pyrazole moiety

ChemInform Abstract: Synthesis of Pyrazoles Based on Functionalized Allenoates.

ChemInformVolume 45, Issue 32 Heterocyclic Compounds ChemInform Abstract: Synthesis of Pyrazoles Based on Functionalized Allenoates. Ilshat M. Sakhautdinov, Ilshat M. Sakhautdinov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorAynur M. Gumerov, Aynur M. Gumerov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorIlnur R. Batyrshin, Ilnur R. Batyrshin Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorAkhnaf A. Fatykhov, Akhnaf A. Fatykhov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorKyrill Yu. Suponitsky, Kyrill Yu. Suponitsky Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorMarat S. Yunusov, Marat S. Yunusov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this author Ilshat M. Sakhautdinov, Ilshat M. Sakhautdinov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorAynur M. Gumerov, Aynur M. Gumerov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorIlnur R. Batyrshin, Ilnur R. Batyrshin Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorAkhnaf A. Fatykhov, Akhnaf A. Fatykhov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorKyrill Yu. Suponitsky, Kyrill Yu. Suponitsky Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this authorMarat S. Yunusov, Marat S. Yunusov Inst. Org. Chem., Ufa Res. Cent., Russ. Acad. Sci., Ufa 450054, RussiaSearch for more papers by this author First published: 24 July 2014 https://doi.org/10.1002/chin.201432142Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume45, Issue32August 12, 2014 RelatedInformation

Synthesis and biological screening of pyrazole moiety containing analogs of podophyllotoxin

The pyrazole moiety containing analogs of podophyllotoxin as potential antimitotic agents were synthesized in five step reactions via chalcone route. The first step is the synthesis of chalcone (2a–d) by the reaction of substituted acetophenones with p-tolualdehyde in the presence of sodium hydroxide in water–ethanol mixture. The cyclopropyl ketones (3a–d) were prepared by the reaction of chalcones (2a–d) with trimethylsulfoxonium iodide (TMSOI) in dry DMSO. The key intermediate tetralones (4a–d) were prepared by the intramolecular cyclization reaction of cyclopropyl ketones (3a–d) in the presence of anhyd. stannic chloride and acetic anhydride in dry dichloromethane. These compounds (4a–d) on formylation give substituted hydroxylmethylene tetralones (5a–d). Further, pyrazole moiety containing analogs of podophyllotoxin (6a–d) were synthesized in high yields by the condensation of hydroxylmethylene tetralones (5a–d) with hydrazine hydrate in absolute ethanol. The structures of the synthesized compounds were confirmed by spectral and elemental analysis data. The synthesized compounds were also screened for their antimitotic activity. It is noteworthy that compounds 6d possessed excellent antimitotic activity, 6b and 6c showed considerable activity, and remaining 6a possessed least activity. Compound 6d was immense to show high antibacterial and antifungal activity against all bacterial and fungal strains compared with standard chloramphenicol and nystatin, respectively.

Synthesis, fastness properties, color assessment and antimicrobial activity of some azo reactive dyes having pyrazole moiety

Some new azo dye derivatives having pyrazole and trichlorotriazine moieties were synthesized and were evaluated as reactive dyes for the exhaust dyeing of cotton fiber. The title dyes 5a–c were synthesized from reactions of diazonium salts of 3-substituted-1-phenyl-5-aminopyrazoles 2a–c with 6-amino-7-hydroxy-2-naphthalenesulfonic acid, 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid and/or cyanuric chloride. Other reactive dyes 7a–f were synthesized from reaction of cyanuric chloride and 4-arylazo-3-substituted-1-phenyl-5-aminopyrazoles 6a–f. The synthesized dyes were applied to cotton fiber and their color fastness to light, washing, perspiration, and rubbing were also measured. The dyes showed good to moderate affinity to cotton fiber. The biological screening showed that most of the tested compounds display promising antimicrobial activities against the tested microorganisms.

Friedel-Crafts chemistry: Part 41. A new facile synthesis of indeno[1,2-c] pyrazoles, 2H-benzo[g]indazoles and benzo[6,7]cyclohepta[1,2-c]pyrazoles via Friedel-Crafts ring closures

Expedient and novel alternative synthesis of some fused heteropolycycles containing pyrazole moiety is described. A series of indeno[1,2- c ]pyrazoles, 2 H -benzo[ g ]indazoles and benzo[6,7] cyclohepta[1,2- c ]pyrazoles were prepared by Friedel-Crafts ring closure of suitable synthesized carboxylic acids and alkanols in the presence of AlCl 3 /CH 3 NO 2 or P 2 O 5 or PPA (polyphosphoric acid) catalysts. The precursor acids were obtained by utilizing KMnO 4 oxidation of the corresponding aldehyde, alkylations of diethyl malonates and Perkin type approaches, whereas starting alkanols were smoothly obtained by reaction of carboxylic acid ester with Grignard reagent. To exemplify, cyclizations of 5-chloro-1,3-diphenyl-1 H -pyrazole-4-carboxylic acid (6) were accomplished using the above catalysts afforded 3-chloro-2-phenylindeno[1,2- c ]pyrazol-4(2 H )-one (1b). Similarly, cyclization of the 2-(5-chloro-1,3-diphenyl-1 H -pyrazol-4-yl)propan-2-ol (8) by a Friedel–Crafts-type ring closure afforded the 3-chloro-2,4-dihydro-4,4-dimethyl-2-phenylindeno[1,2- c ]pyrazole (1a).

ChemInform Abstract: Synthesis, Antibacterial and Antifungal Activities of Some New Azo Anils Containing Pyrazole Moiety.

AbstractA series of title compounds of type (III), (VI), and (VII) are prepared and tested for their antibacterial and antifungal activities.

How Cocrystallization Affects Solid-State Tautomerism: Stanozolol Case Study

Three original cocrystals of stanozolol with monoacidic and diacidic coformers are presented and fully characterized in this study. Powder X-ray diffraction (PXRD) permits cocrystal formation to be highlighted, with the help of liquid-assisted grinding (LAG) from the two starting coformers. Single-crystal X-ray diffraction (SCXRD) gives a detailed structural characterization, which allows comparison with existing structures coming from the Cambridge Structural Database (essentially stanozolol solvates) and determination of structural similarities between the new cocrystal structures and the existing ones. As stanozolol can exist under two tautomeric forms (on its pyrazole moiety), statistical and theoretical studies have been performed in order to better apprehend the potential appearance of one of its tautomers at the cost of the other in crystal structures, and the eventuality of “freezing” the molecule in one of these forms by cocrystallization.

Discovery of a potent, selective, and orally active phosphodiesterase 10A inhibitor for the potential treatment of schizophrenia.

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

ChemInform Abstract: Synthesis and Characterization of Some Heteroaromatic Derivatives of 3‐But‐2‐enoyl‐chromen‐2‐one and Their Potential as Antiinflammatory Agents.

AbstractA variety of novel chromen‐2‐one derivatives containing pyrazole, isoxazole, oxazine and thiazine moieties are synthesized starting from chalcone (V).

Synthesis and antibacterial and cytotoxic activities of new N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety.

Two new series of N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety (5a-j and 7a-j) were synthesized and assessed in vitro for their efficacy as antibacterial agents against gram-positive and gram-negative bacterial strains. Among the tested compounds, 7b, 7c, 7i, and 7j were found to be active against gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes) with minimum inhibitory concentration (MIC) values in the range of 6.25-25 µg/mL, and some compounds were also tested against methicillin-resistant S. aureus (MRSA). Compounds 7c and 7j inhibited the growth of MRSA at MIC values of 6.25 and 12.5 µg/mL, respectively. The influence of the lipophilicity (C log P) on the biological profile (MIC) of the prepared products was also discussed. From the standpoint of structure-activity relationship studies, it was observed that the lipophilic profiles of the compounds were crucial for their antibacterial activities. Further, the results of the MTT cytotoxicity studies on a human cervical cancer cell line (HeLa) and a mouse embryonic fibroblast cell line (NIH 3T3) suggested that compounds 7b, 7c, 7i, and 7j were endowed with low levels of cytotoxicity.

Synthesis and anti-breast cancer evaluation of novel N-(guanidinyl)benzenesulfonamides.

A series of 4-(substituted)-N-(guanidinyl)benzenesulfonamides bearing biologically active pyrazole, pyrimidine and pyridine moieties were prepared and evaluated for their anticancer activity against human tumor breast cell line (MCF7). These sulfonamides showed promising activity with IC50 values ranging from 49.5 to 70.2 μM. The structure-activity relationship of the synthesized compounds was studied. Interestingly, it was found that the most potent compounds in this study were the corresponding 2-cyanoacrylate 3, 3-oxobutanoate 4, pyrazole 6, pyridine 9 and pyrazole 13. Compounds 7 and 8 are nearly as active as Doxorubicin as reference drug with (IC50 values = 70.2, 68.1 μM), while compounds 5, 10 and 11 exhibited a moderate activity.