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The Journal of Organic Chemistry Jan 2022Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of...
Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole -oxides with arynes using mild conditions. Importantly, this method does not require the C4 and C5 positions of the pyrazole to be functionalized to observe regioselectivity. Using this method, we completed the synthesis of a recently reported JAK 1/2 inhibitor. Our synthesis produces the desired product in 4 steps from commercially available starting materials.
Topics: Molecular Structure; Pyrazoles
PubMed: 34905376
DOI: 10.1021/acs.joc.1c02518 -
Archiv Der Pharmazie Feb 2022Novel series of pyrazolo[3,4-b]pyridines 9a-j and 14a-f were prepared via a one-pot three-component reaction. Compounds 9a-j were synthesized by the reaction of...
Novel series of pyrazolo[3,4-b]pyridines 9a-j and 14a-f were prepared via a one-pot three-component reaction. Compounds 9a-j were synthesized by the reaction of 3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-amine (4) with benzoyl acetonitriles 3a,b and aldehydes 5a-e, whereas the spiro derivatives 14a-f were synthesized by the reaction of pyrazole derivative 4 with 3a-c and indoline-2,3-diones 10a,b. Screening of the antiproliferative activity of 9a-j and 14a-f revealed that 14a and 14d were the most potent analogues against HepG2 and HeLa cells, with IC = 4.2 and 5.9 μM, respectively. Moreover, compounds 9c and 14a could promote cell cycle disturbance and apoptosis in HepG2 cells, as evidenced by DNA flow cytometry and Annexin V-FITC/PI assays. Cell cycle analysis of 9c and 14a indicated a reduction in HepG2 cells in the G1 phase, with arrest in the S phase and the G2/M phase, respectively. Also, 9c and 14a are good apoptotic inducers in the HepG2 cell line. Furthermore, compounds 9h and 14d stood out as the most efficient antiproliferative agents in the NCI 60-cell line panel screening, with mean GI % equal to 60.3% and 55.4%, respectively. Additionally, 9c, 9h, 14a, and 14d showed good inhibitory action against the cellular pathway regulator p38α kinase, with IC = 0.42, 0.41, 0.13, and 0.64 μM, respectively. A docking study was carried out on the p38α kinase active site, showing a binding mode comparable to that of reported p38 mitogen-activated protein kinase inhibitors. These newly discovered pyrazolo[3,4-b]pyridines could be considered as potential candidates for the development of newly targeted anticancer agents.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; HeLa Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; Mitogen-Activated Protein Kinase 14; Molecular Docking Simulation; Pyrazoles; Pyridines; Structure-Activity Relationship
PubMed: 34796536
DOI: 10.1002/ardp.202100302 -
European Journal of Medicinal Chemistry Jul 2021A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for...
A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for antibacterial activity. The majority of trifluoromethyl phenyl derivatives are highly potent growth inhibitors of Gram-positive bacteria and showed low toxicity to human cultured cells. In particular, two compounds (59 and 74) were selected for additional studies. These compounds are highly effective against Staphylococcus aureus as shown by a low minimum inhibitory concentration (MIC), a bactericidal effect in time-kill assays, moderate inhibition of biofilm formation as well as biofilm destruction, and a bactericidal effect against stationary phase cells representing non-growing persister cells. Multistep resistance assays showed a very low tendency for S. aureus and Enterococcus faecalis to develop resistance through mutation. Additionally, in vivo mouse model studies showed no harmful effects at doses up to 50 mg/kg using 14 blood plasma organ toxicity markers or TUNEL assay in liver and kidney. Investigations into the mode of action by performing macromolecular synthesis inhibition studies showed a broad range of inhibitory effects, suggesting targets that have a global effect on bacterial cell function.
Topics: Aniline Compounds; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Drug Resistance, Bacterial; Enterococcus faecalis; Gram-Positive Bacteria; Humans; Liver; Microbial Sensitivity Tests; Pyrazoles; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 33845234
DOI: 10.1016/j.ejmech.2021.113402 -
Molecules (Basel, Switzerland) Aug 2022Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected...
Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and pyrazole-containing chemotypes demonstrated activity against parasites. This study reports the synthesis and structure of trioxolane-pyrazole (, ) and tetraoxane-pyrazole (, ) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for antileishmanial activity against promastigotes of and , and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of Trioxolane-pyrazole hybrids and exhibited some activity against promastigotes, while tetraoxane-pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound was the most active against both strains of . Such finding was corroborated by the results obtained in assessments of the amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide-pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of . Our preliminary biological findings encourage further optimization of peroxide-pyrazole hybrids to identify a promising antileishmanial lead.
Topics: Antiprotozoal Agents; Humans; Leishmania; Leishmania infantum; Leishmaniasis; Pyrazoles; Tetraoxanes
PubMed: 36080174
DOI: 10.3390/molecules27175401 -
Medicinal Chemistry (Shariqah (United... 2022Pyrazole is a component of a diversity of bioactive heterocyclic congeners with a broad-spectrum range of biological and pharmacological uses. Designing novel pyrazole...
BACKGROUND
Pyrazole is a component of a diversity of bioactive heterocyclic congeners with a broad-spectrum range of biological and pharmacological uses. Designing novel pyrazole and its analogues, revealing new routes for synthesizing this nucleus, exploring various potencies of that heterocycles, and looking for possible applications of pyrazoles are all becoming more important due to their numerous potential applications.
OBJECTIVES
Pyrazole scaffolds have been proven to be successful as anti-viral and anti-inflammatory therapeutics against multiple targets like HSV-1, NNRTI, H1N1, CoX-1, and CoX-2. Due to this miscellany in the biotic area, this moiety has engrossed the consideration of many scientists to study chemistry and pharmacological profile.
RESULTS
The review encompasses pyrazole having various scaffolds with multiple biological activities and attempts have also been made to correlate their structure-activity relationship. Multiple pyrazole correspondents have been synthesized as lead molecules and performed valuation for their actions.
CONCLUSION
The incorporation of pyrazole with other pharmacophores in the molecule might lead to novel potent therapeutic agents that will further help in designing potent lead molecules.
Topics: Anti-Inflammatory Agents; Antiviral Agents; Drug Design; Influenza A Virus, H1N1 Subtype; Pyrazoles; Structure-Activity Relationship
PubMed: 35410619
DOI: 10.2174/1573406418666220410181827 -
Chemical Communications (Cambridge,... Apr 2022Indazole and pyrazole are renowned as a prodigious class of heterocycles having versatile uses in medicinal as well as industrial chemistry. Considering sustainable... (Review)
Review
Indazole and pyrazole are renowned as a prodigious class of heterocycles having versatile uses in medicinal as well as industrial chemistry. Considering sustainable approaches, recently, photocatalysis has become an indispensable tool in organic chemistry due to its application for the activation of small molecules and the use of a clean energy source. In this review, we have highlighted the use of metal-based photocatalysts, organic photoredox catalysts, energy transfer photocatalysts and electron-donor-acceptor complexes in the functionalization of indazole and pyrazole. This perspective is arranged based on the types of functionalization reactions on indazole and pyrazole. A detailed discussion regarding the reaction mechanism of each reaction is given to provide a comprehensive guide to the reader. Finally, a summary of existing challenges and the future outlook towards the development of efficient photocatalytic methods for functionalization of these heterocycles is also presented.
Topics: Catalysis; Indazoles; Light; Pyrazoles
PubMed: 35294515
DOI: 10.1039/d2cc00002d -
Molecules (Basel, Switzerland) Jan 2022Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have... (Review)
Review
Pyrazole has been recognized as a pharmacologically important privileged scaffold whose derivatives produce almost all types of pharmacological activities and have attracted much attention in the last decades. Of the various pyrazole derivatives reported as potential therapeutic agents, this article focuses on pyrazole-based kinase inhibitors. Pyrazole-possessing kinase inhibitors play a crucial role in various disease areas, especially in many cancer types such as lymphoma, breast cancer, melanoma, cervical cancer, and others in addition to inflammation and neurodegenerative disorders. In this article, we reviewed the structural and biological characteristics of the pyrazole derivatives recently reported as kinase inhibitors and classified them according to their target kinases in a chronological order. We reviewed the reports including pyrazole derivatives as kinase inhibitors published during the past decade (2011-2020).
Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Drug Development; Enzyme Inhibitors; History, 21st Century; Humans; Immune Checkpoint Inhibitors; Models, Molecular; Protein Kinase Inhibitors; Pyrazoles; Signal Transduction; Structure-Activity Relationship
PubMed: 35011562
DOI: 10.3390/molecules27010330 -
Journal of Medicinal Chemistry Jan 2021A series of 1-methyl-1-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, . These compounds did not show overt...
A series of 1-methyl-1-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, . These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.
Topics: Animals; Antiprotozoal Agents; Cell Survival; Drug Evaluation, Preclinical; Female; Haemonchus; Male; Mice; Mitochondria; Pyrazoles; Rats; Sheep; Structure-Activity Relationship
PubMed: 33352050
DOI: 10.1021/acs.jmedchem.0c01793 -
Analytical Methods : Advancing Methods... Jan 2022Ruxolitinib, a kinase inhibitor, was subjected to stress studies as described in the ICH Q1A(R2) guidelines. Solution state hydrolytic and solid state oxidative and...
Ruxolitinib, a kinase inhibitor, was subjected to stress studies as described in the ICH Q1A(R2) guidelines. Solution state hydrolytic and solid state oxidative and thermal stress studies were carried out to understand its degradation behaviour. The drug showed significant instability in the hydrolytic condition in comparison with other conditions. HPLC and UHPLC methods were developed for the separation of the drug and its hydrolytic degradation products. Mass fragmentation pathway of the drug was established as the first step of the LC-MS characterization of the degradation products. MS/MS analysis of the drug and MS of selected fragments were achieved through QTOF and QTRAP by varying the collision energy and performing an H/D exchange. LC-MS/MS QTOF studies were subsequently carried out on stress samples and the structures of the degradation products were identified through comparison of the drug fragmentation pathways. The four hydrolytic products 4-(1-pyrazol-4-yl)-7-pyrrolo[2,3-]pyrimidine, 3-(4-(7-pyrrolo[2,3-]pyrimidin-4-yl)-1-pyrazol-1-yl)-3-cyclopentylpropanoic acid, 3-(4-(7-pyrrolo[2,3-]pyrimidin-4-yl)-1-pyrazol-1-yl)-3-cyclopentylpropanamide, and 3-(4-(6-amino-5-formylpyrimidin-4-yl)-1-pyrazol-1-yl)-3-cyclopentylpropanenitrile were formed under acidic and basic conditions. The degradation pathway was delineated through a mechanistic explanation. The tools preADMET and Protox-II predictor were used to compare the toxicity of the impurities with respect to the drug.
Topics: Chromatography, Liquid; Drug Development; Drug Stability; Nitriles; Pyrazoles; Pyrimidines; Tandem Mass Spectrometry
PubMed: 34989722
DOI: 10.1039/d1ay01915e -
Methods (San Diego, Calif.) Jun 2023Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics....
Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity.
Topics: alpha-Synuclein; Pyrazoles; Benzodioxoles; Magnetic Resonance Spectroscopy; Protein Aggregates
PubMed: 37037308
DOI: 10.1016/j.ymeth.2023.04.002