Molecules

Research

Jump to: Review

15 pages, 2320 KiB

Open AccessArticle

Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations

by Gábor J. Szebeni, József A. Balog, András Demjén, Róbert Alföldi, Vanessza L. Végi, Liliána Z. Fehér, Imola Mán, Edit Kotogány, Barbara Gubán, Péter Batár, László Hackler, Iván Kanizsai and László G. Puskás

Molecules 2018, 23(11), 2845; https://doi.org/10.3390/molecules23112845 - 1 Nov 2018

Cited by 15 | Viewed by 3879

Abstract

Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2-b]pyrazole-7-carboxamides have been tested for cytotoxic [...] Read more.

Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2-b]pyrazole-7-carboxamides have been tested for cytotoxic activity against five leukemia cell lines: Acute promyelocytic leukemia (HL-60), acute monocytic leukemia (THP-1), acute T-lymphoblastic leukemia (MOLT-4), biphenotypic B myelomonocytic leukemia (MV-4-11), and erythroleukemia (K-562) cells in vitro. Imidazo[1,2-b]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC₅₀ values for the most effective lead compound DU385: 16.54 nM, 27.24 nM, and 32.25 nM on HL-60, MOLT-4, MV-4-11 cells, respectively. Human primary fibroblasts were much less sensitive in the applied concentration range. Both monolayer or spheroid cultures of murine 4T1 and human MCF7 breast cancer cells were less sensitive to treatment with 1.5–10.8 μM IC₅₀ values. Flow cytometry confirmed the absence of necrosis and revealed 60% late apoptotic population for MV-4-11, and 50% early apoptotic population for HL-60. MOLT-4 cells showed only about 30% of total apoptotic population. Toxicogenomic study of DU385 on the most sensitive MV-4-11 cells revealed altered expression of sixteen genes as early (6 h), midterm (12 h), and late response (24 h) genes upon treatment. Changes in ALOX5AP, TXN, and SOD1 expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2-b]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

12 pages, 1020 KiB

Open AccessArticle

Design, Synthesis, and Antimicrobial Evaluation of Novel Pyrazoles and Pyrazolyl 1,3,4-Thiadiazine Derivatives

by Ibrahim Ali M. Radini

Molecules 2018, 23(9), 2092; https://doi.org/10.3390/molecules23092092 - 21 Aug 2018

Cited by 20 | Viewed by 3888

Abstract

A novel series of pyrazolyl 1,3,4-thiadiazines 5a–c, 8a–c, 12, 15a–c, 17a–c, and 20 was prepared from the reaction of pyrazole-1-carbothiohydrazide 1a,b with 2-oxo-N′-arylpropanehydrazonoyl chloride, 2-chloro-2-(2-arylhydrazono)acetate, and [...] Read more.

A novel series of pyrazolyl 1,3,4-thiadiazines 5a–c, 8a–c, 12, 15a–c, 17a–c, and 20 was prepared from the reaction of pyrazole-1-carbothiohydrazide 1a,b with 2-oxo-N′-arylpropanehydrazonoyl chloride, 2-chloro-2-(2-arylhydrazono)acetate, and 3-bromoacetylcoumarin. Moreover, the regioselective reaction of 5-pyrazolone-1-carbothiohydrazide 1a with 4-substituted diazonium salts and 4-(dimethylamino)benzaldehyde gave the corresponding hydrazones 21a–c and 22. The newly prepared compounds were characterized by spectroscopy and elemental analysis. Many new synthesized compounds showed considerable antimicrobial activity against tested microorganisms. Hydrazones 21a–c and 22 showed remarkable antibacterial and antifungal activities. 4-(2-(p-tolyl)hydrazineylidene)-pyrazole-1-carbothiohydrazide 21a displayed the highest antibacterial and antifungal activities with minimum inhibitory concentration (MIC) values lower than standard drugs chloramphenicol and clotrimazole, in the range of 62.5–125 and 2.9–7.8 µg/mL, respectively. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

9 pages, 1463 KiB

Open AccessArticle

Discovery of 4,5-Dihydro-1H-thieno[2′,3′:2,3]thiepino [4,5-c]pyrazole-3-carboxamide Derivatives as the Potential Epidermal Growth Factor Receptors for Tyrosine Kinase Inhibitors

by Jia Ke, Qi Lu, Xin Wang, Rui Sun, Zhe Jin, Xiaoyi Zhan, Jianshu Hu, David Chi-cheong Wan and Chun Hu

Molecules 2018, 23(8), 1980; https://doi.org/10.3390/molecules23081980 - 8 Aug 2018

Cited by 7 | Viewed by 3122

Abstract

The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a [...] Read more.

The epidermal growth factor receptors (EGFRs), in which overexpression (known as upregulation) or overactivity have been associated with a number of cancers, has become an attractive molecular target for the treatment of selective cancers. We report here the design and synthesis of a novel series of 4,5-dihydro-1H-thieno [2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives and the screening for their inhibitory activity on the EGFR high-expressing human A549 cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). A Docking simulation was performed to fit compound 6g and gifitinib into the EGFR to determine the probable binding models, and the binding sites and modes conformation of 6g and gifitinib were exactly similar, the two compounds were stabilized by hydrogen bond interactions with MET769. Combining with the biological activity evaluation, compound 6g demonstrated the most potent inhibitory activity (IC₅₀ = 9.68 ± 1.95 μmol·L^–1 for A549). Conclusively, 4,5-dihydro-1H-thieno[2′,3′:2,3]thiepino[4,5-c]pyrazole-3-carboxamide derivatives as the EGFR tyrosine kinase inhibitors were discovered, and could be used as potential lead compounds against cancer cells. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

14 pages, 2262 KiB

Open AccessArticle

Modification of Boc-Protected CAN508 via Acylation and Suzuki-Miyaura Coupling

by Martin Pisár, Eva Schütznerová, Filip Hančík, Igor Popa, Zdeněk Trávníček and Petr Cankař

Molecules 2018, 23(1), 149; https://doi.org/10.3390/molecules23010149 - 12 Jan 2018

Cited by 2 | Viewed by 5890

Abstract

The cyclin-dependent kinase inhibitor, CAN508, was protected with di-tert-butyl dicarbonate to access the amino-benzoylated pyrazoles. The bromo derivatives were further arylated by Suzuki-Miyaura coupling using the XPhos Pd G2 pre-catalyst. The coupling reaction provided generally the para-substituted benzoylpyrazoles in the [...] Read more.

The cyclin-dependent kinase inhibitor, CAN508, was protected with di-tert-butyl dicarbonate to access the amino-benzoylated pyrazoles. The bromo derivatives were further arylated by Suzuki-Miyaura coupling using the XPhos Pd G2 pre-catalyst. The coupling reaction provided generally the para-substituted benzoylpyrazoles in the higher yields than the meta-substituted ones. The Boc groups were only utilized as directing functionalities for the benzoylation step and were hydrolyzed under conditions of Suzuki-Miyaura coupling, which allowed for elimination of the additional deprotection step. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Figure 1

15 pages, 2466 KiB

Open AccessFeature PaperArticle

On the Tautomerism of N-Substituted Pyrazolones: 1,2-Dihydro-3H-pyrazol-3-ones versus 1H-Pyrazol-3-ols

by Eglė Arbačiauskienė, Sonata Krikštolaitytė, Aiva Mitrulevičienė, Aurimas Bieliauskas, Vytas Martynaitis, Matthias Bechmann, Alexander Roller, Algirdas Šačkus and Wolfgang Holzer

Molecules 2018, 23(1), 129; https://doi.org/10.3390/molecules23010129 - 9 Jan 2018

Cited by 20 | Viewed by 6053

Abstract

The tautomerism of 1-phenyl-1,2-dihydro-3H-pyrazol-3-One was investigated. An X-ray crystal structure analysis exhibits dimers of 1-phenyl-1H-pyrazol-3-ol units. Comparison of NMR (nuclear magnetic resonance) spectra in liquid state (¹H, ¹³C, ¹⁵N) with those of “fixed” derivatives, as [...] Read more.

The tautomerism of 1-phenyl-1,2-dihydro-3H-pyrazol-3-One was investigated. An X-ray crystal structure analysis exhibits dimers of 1-phenyl-1H-pyrazol-3-ol units. Comparison of NMR (nuclear magnetic resonance) spectra in liquid state (¹H, ¹³C, ¹⁵N) with those of “fixed” derivatives, as well as with the corresponding solid state NMR spectra reveal this compound to exist predominantly as 1H-pyrazol-3-ol molecule pairs in nonpolar solvents like CDCl₃ or C₆D₆, whereas in DMSO-d₆ the corresponding monomers are at hand. Moreover, the NMR data of different related 1H-pyrazol-3-ol derivatives are presented. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

5516 KiB

Open AccessArticle

Synthesis, Crystal Structure, and Supramolecular Understanding of 1,3,5-Tris(1-phenyl-1H-pyrazol-5-yl)benzenes

by Marcos A. P. Martins, Alexandre R. Meyer, Paulo R. S. Salbego, Daniel M. Dos Santos, Guilherme A. De Moraes, Helio G. Bonacorso, Nilo Zanatta, Clarissa P. Frizzo and Manfredo Hörner

Molecules 2018, 23(1), 22; https://doi.org/10.3390/molecules23010022 - 22 Dec 2017

Cited by 4 | Viewed by 5185

Abstract

Understanding the supramolecular environment of crystal structures is necessary to facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular structures of pyrazoles. This class [...] Read more.

Understanding the supramolecular environment of crystal structures is necessary to facilitate designing molecules with desirable properties. A series of 12 novel 1,3,5-tris(1-phenyl-1H-pyrazol-5-yl)benzenes was used to assess the existence of planar stacking columns in supramolecular structures of pyrazoles. This class of molecules with different substituents may assist in understanding how small structural changes affect the supramolecular environment. The obtained compounds did not present the formation of planar stacking interactions between benzenes in solid or liquid states. This supposition was indicated by single crystal diffraction, Density Functional Theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations, and concentration-dependent liquid-state ¹H nuclear magnetic resonance (NMR). NMR showed that chemical shifts of benzene and pyrazole hydrogens confirm that planar stacking interactions are not formed in solution. The crystalline structures presented different molecular conformations. The molecular structures of 5 and 9b are in a twisted conformation, while compound 7 showed a conformation analogous to a calyx form. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

2347 KiB

Open AccessArticle

¹⁹F‐NMR Diastereotopic Signals in Two N-CHF₂ Derivatives of (4S,7R)-7,8,8-Trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole

by Diana García-Pérez, Concepción López, Rosa M. Claramunt, Ibon Alkorta and José Elguero

Molecules 2017, 22(11), 2003; https://doi.org/10.3390/molecules22112003 - 17 Nov 2017

Cited by 9 | Viewed by 8371

Abstract

In this paper, we report the anisochrony of the fluorine atoms of a CHF₂ group when linked to a pyrazole ring. The pyrazole is part of (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole also known as (4S,7R)-campho[2,3-c [...] Read more.

In this paper, we report the anisochrony of the fluorine atoms of a CHF₂ group when linked to a pyrazole ring. The pyrazole is part of (4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole also known as (4S,7R)-campho[2,3-c]pyrazole, which has two stereogenic centers. Gauge-Independent Atomic Orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,f) calculated ¹⁹F chemical shifts of the minimum energy conformations satisfactorily agree with the experimental data. The energy differences between minima need to consider solvent effects (continuum model) to be satisfactorily reproduced. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

2483 KiB

Open AccessArticle

Synthesis and Structure–Activity Relationships of 4-Morpholino-7,8-Dihydro-5H-Thiopyrano[4,3-d]pyrimidine Derivatives Bearing Pyrazoline Scaffold

by Qinqin Wang, Xiaojing Li, Chengyu Sun, Binliang Zhang, Pengwu Zheng, Wufu Zhu and Shan Xu

Molecules 2017, 22(11), 1870; https://doi.org/10.3390/molecules22111870 - 31 Oct 2017

Cited by 12 | Viewed by 4509

Abstract

Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is abnormally active in the growth and proliferation of cancer cells. The inhibition of PI3K kinase can effectively block the conduction of signaling pathways and is an ideal target for drug design. In [...] Read more.

Phosphatidylinositol 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is abnormally active in the growth and proliferation of cancer cells. The inhibition of PI3K kinase can effectively block the conduction of signaling pathways and is an ideal target for drug design. In this paper; two series of 4-morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing pyrazoline moiety (7a–l; 8a–l) were synthesized; and their cytotoxicity in vitro were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method against four human cancer cell lines including A549; PC-3; MCF-7; and HepG2 cell lines. The activity of the most promising compound 8d against PI3Kα kinase was further evaluated. The results indicated that most of the target compounds showed moderate to excellent cytotoxicity and the most promising compound 8d showed excellent cytotoxicity against four cancer cell lines with half maximal inhibitory concentration (IC₅₀) values of 6.02–10.27 μM. In addition; the compound 8d was found to have a moderate inhibitory activity in the PI3Kα enzyme assay. What’s more; the compounds of which the substituents of benzene ring at the C-4 position are electron-withdrawing groups such as substituents (Cl; F; Br) have better activity than the compounds containing the electron donating groups (OCH₃; H). However; the exact action mechanism is not quite clear right now. Further study will be carried out to identify the exact target in near future. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

2489 KiB

Open AccessArticle

Solvent and Copper Ion-Induced Synthesis of Pyridyl–Pyrazole-3-One Derivatives: Crystal Structure, Cytotoxicity

by Qiu Ping Huang, Shao Nan Zhang, Shu Hua Zhang, Kai Wang and Yu Xiao

Molecules 2017, 22(11), 1813; https://doi.org/10.3390/molecules22111813 - 25 Oct 2017

Cited by 12 | Viewed by 4453

Abstract

Five novel compounds, methyl 5-(acetyloxy)-1-(6-bromo-2-pyridinyl)-1H-pyrazole-3-carboxylate (1), methyl 1-(6-bromo-2-pyridinyl)-5-hydroxy-1H-pyrazole-3-carboxylate (2), Trimethyl 1,1′,1′′-tris(6-bromo-2-pyridinyl)-5,5′′-dihydroxy-5′-oxo-1′,5′-dihydro-1H,1′′H-4,4′: 4′,4′′-terpyrazole-3,3′,3′′-tricarboxylate (H₂L¹, 3), [Cu₂(L²)₂]·CH₃OH (4), H₂L^2A·CH₃ [...] Read more.

Five novel compounds, methyl 5-(acetyloxy)-1-(6-bromo-2-pyridinyl)-1H-pyrazole-3-carboxylate (1), methyl 1-(6-bromo-2-pyridinyl)-5-hydroxy-1H-pyrazole-3-carboxylate (2), Trimethyl 1,1′,1′′-tris(6-bromo-2-pyridinyl)-5,5′′-dihydroxy-5′-oxo-1′,5′-dihydro-1H,1′′H-4,4′: 4′,4′′-terpyrazole-3,3′,3′′-tricarboxylate (H₂L¹, 3), [Cu₂(L²)₂]·CH₃OH (4), H₂L^2A·CH₃CN (5) were synthesized. Compounds 1–5 characterized by elemental analysis, IR, and X-ray single-crystal diffraction. And 1–3 were also characterized by ¹H NMR, ¹³C NMR and ESI-MS. The H₂L¹, H₂L² were formed by in-situ reaction. H₂L² and H₂L^2A are mesomer compounds which have two chiral carbons. The antitumor activity of compounds 1–5 against BEL-7404, HepG2, NCI-H460, T-24, A549 tumor cell lines were screened by methylthiazolyl tetrozolium (MTT) assay. The compounds 1, 2 showed weakly growth inhibition on the HepG2 cell lines. The HepG2 and A549 cell lines showed higher sensitivity to compound 4, while the IC₅₀ values are 10.66, 28.09 μM, respectively. It is worth noting that compounds 1–5 did not show cytotoxicity to human normal liver cell line HL-7702, suggesting its cytotoxic selectivity on these tumor cell lines. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Graphical abstract

Review

Jump to: Research

86 pages, 35179 KiB

Open AccessReview

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

by Khalid Karrouchi, Smaail Radi, Youssef Ramli, Jamal Taoufik, Yahia N. Mabkhot, Faiz A. Al-aizari and M’hammed Ansar

Molecules 2018, 23(1), 134; https://doi.org/10.3390/molecules23010134 - 12 Jan 2018

Cited by 710 | Viewed by 39053

Abstract

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug [...] Read more.

Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Figure 1

8603 KiB

Open AccessReview

Synthesis of Non-Racemic Pyrazolines and Pyrazolidines by [3+2] Cycloadditions of Azomethine Imines

by Franc Požgan, Hamad Al Mamari, Uroš Grošelj, Jurij Svete and Bogdan Štefane

Molecules 2018, 23(1), 3; https://doi.org/10.3390/molecules23010003 - 21 Dec 2017

Cited by 23 | Viewed by 6844

Abstract

Asymmetric [3+2] cycloadditions of azomethine imines comprise a useful synthetic tool for the construction of pyrazole derivatives with a variable degree of saturation and up to three stereogenic centers. As analogues of pyrrolidines and imidazolidines that are abundant among natural products, pyrazoline and [...] Read more.

Asymmetric [3+2] cycloadditions of azomethine imines comprise a useful synthetic tool for the construction of pyrazole derivatives with a variable degree of saturation and up to three stereogenic centers. As analogues of pyrrolidines and imidazolidines that are abundant among natural products, pyrazoline and pyrazolidine derivatives represent attractive synthetic targets due to their extensive applications in the chemical and medicinal industries. Following the increased understanding of the mechanistic aspect of metal-catalyzed and organocatalyzed [3+2] cycloadditions of 1,3-dipoles gained over recent years, significant strides have been taken to design and develop new protocols that proceed efficiently under mild synthetic conditions and duly benefit from superior functional group tolerance and selectivity. In this review, we represent the current state of the art in this field and detailed methods for the synthesis of non-racemic pyrazolines and pyrazolidines via [3+2] metal and organocatalyzed transformations reported since the seminal work of Kobayashi et al. and Fu et al. in 2002 and 2003 up to the end of year 2017. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Figure 1

25027 KiB

Open AccessReview

Synthesis of Chromone-Related Pyrazole Compounds

by Clementina M. M. Santos, Vera L. M. Silva and Artur M. S. Silva

Molecules 2017, 22(10), 1665; https://doi.org/10.3390/molecules22101665 - 5 Oct 2017

Cited by 37 | Viewed by 12713

Abstract

Chromones, six-membered oxygen heterocycles, and pyrazoles, five-membered two-adjacentnitrogen- containing heterocycles, represent two important classes of biologically active compounds. Certain derivatives of these scaffolds play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis. In [...] Read more.

Chromones, six-membered oxygen heterocycles, and pyrazoles, five-membered two-adjacentnitrogen- containing heterocycles, represent two important classes of biologically active compounds. Certain derivatives of these scaffolds play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis. In this context, we will discuss the most relevant advances on the chemistry that involves both chromone and pyrazole rings. The methods reviewed include the synthesis of chromone-pyrazole dyads, synthesis of chromone-pyrazole-fused compounds, and chromones as starting materials in the synthesis of 3(5)-(2-hydroxyaryl)pyrazoles, among others. This review will cover the literature on the chromone and pyrazole dual chemistry and their outcomes in the 21st century. Full article

(This article belongs to the Special Issue Pyrazole Derivatives)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Pyrazole Derivatives

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (12 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI