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European Journal of Medicinal Chemistry Oct 2017One-third of the world's population infected tuberculosis (TB), and more than 1 million deaths annually. The co-infection between the mainly pathogen Mycobacterium... (Review)
Review
One-third of the world's population infected tuberculosis (TB), and more than 1 million deaths annually. The co-infection between the mainly pathogen Mycobacterium tuberculosis (MTB) and HIV, and the incidence of drug-resistant TB, multi-drug resistant TB, extensively drug-resistant TB as well as totally drug-resistant TB have further aggravated the mortality and spread of this disease. Thus, there is an urgent need to develop novel anti-TB agents against both drug-susceptible and drug-resistant TB. The wide spectrum of biological activities and successful utilization of pyrazole-containing drugs in clinic have inspired more and more attention towards this kind of heterocycles. Numerous of pyrazole-containing derivatives have been synthesized for searching new anti-TB agents, and some of them showed promising potency and may have novel mechanism of action. This review aims to outline the recent achievements in pyrazole-containing derivatives as anti-TB agents and their structure-activity relationship.
Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles; Structure-Activity Relationship; Tuberculosis
PubMed: 28818767
DOI: 10.1016/j.ejmech.2017.07.059 -
Molecules (Basel, Switzerland) Jul 2023The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases... (Review)
Review
The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.
Topics: Pyrazoles; Protein Kinase Inhibitors; Antineoplastic Agents; Drug Design; Structure-Activity Relationship; Humans; Animals
PubMed: 37513232
DOI: 10.3390/molecules28145359 -
Bioorganic & Medicinal Chemistry Letters Jul 2014Various substituted 4,6-diarylpyrimidin-2-amine (4), 4,6-diaryl-2-(heteroaryl)pyrimidine (6) and 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7) derivatives were...
Various substituted 4,6-diarylpyrimidin-2-amine (4), 4,6-diaryl-2-(heteroaryl)pyrimidine (6) and 1-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)ethanone (7) derivatives were synthesized in good yields using simple methodology. The synthesized compounds (4-7) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Compounds 4a, 6b, 7b, and 7c exhibited significant anti-tubercular activity at MIC values 25, 25, 12.5 and 12.5 μM concentration. In vitro cytotoxicity data using non cancerous hepatic monocytes (THP-1) cells indicated that most active compounds 7b and 7c were safe as their MIC values were much lower than their cytotoxic values.
Topics: Antitubercular Agents; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles; Pyrimidines; Structure-Activity Relationship
PubMed: 24835631
DOI: 10.1016/j.bmcl.2014.04.094 -
Bioorganic & Medicinal Chemistry Apr 2013In this study, twenty 3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives with hydroxyl(s) (1a-1p, 2a-2d) were synthesized and their inhibitory activity on mushroom...
In this study, twenty 3,5-diaryl-4,5-dihydro-1H-pyrazole derivatives with hydroxyl(s) (1a-1p, 2a-2d) were synthesized and their inhibitory activity on mushroom tyrosinase was examined. The results showed that among these compounds, 1-(5-(3,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone 1d was found to be the most potent tyrosinase inhibitor with IC50 value of 0.301 μM. Kinetic study revealed that these compounds were competitive inhibitors of tyrosinase and their structure-activity relationships were investigated in this article.
Topics: Agaricales; Enzyme Inhibitors; Kinetics; Monophenol Monooxygenase; Pyrazoles; Structure-Activity Relationship
PubMed: 23391365
DOI: 10.1016/j.bmc.2012.12.054 -
Biochemical Pharmacology Mar 2024Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells... (Review)
Review
Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells characteristics that promote the growth of malignant tumours, including genomic instability and mutations, the ability to evade cellular death and the capacity of sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) is a protein that plays key roles in cellular regulation, namely in DNA damage repair and cell survival. The inhibition of PARP1 promotes cellular death in cells with homologous recombination deficiency, and therefore, the interest in PARP protein has been rising as a target for anticancer therapies. There are already some PARP1 inhibitors approved by Food and Drug Administration (FDA), such as Olaparib and Niraparib. The last compound presents in its structure an indazole core. In fact, pyrazoles and indazoles have been raising interest due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as inhibitors of PARP1 and presented promising results. Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors.
Topics: Adenosine Diphosphate Ribose; Cell Cycle; Indazoles; Neoplasms; Pyrazoles; United States; Humans; Animals; Poly (ADP-Ribose) Polymerase-1
PubMed: 38336156
DOI: 10.1016/j.bcp.2024.116045 -
Angewandte Chemie (International Ed. in... Jun 2015The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic...
The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib.
Topics: Alkadienes; Catalysis; Nitriles; Nitrogen; Pyrazoles; Pyrimidines; Rhodium; Stereoisomerism
PubMed: 25926026
DOI: 10.1002/anie.201501758 -
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 -
Organic Letters Aug 2020The hydrazine group serves as a great anchor for bioconjugation; however, the application of hydrazone ligation has been limited by poor product stability. We aim to...
The hydrazine group serves as a great anchor for bioconjugation; however, the application of hydrazone ligation has been limited by poor product stability. We aim to resolve such issues by optimizing the recently established pyrazolone ligation and investigating a new pyrazole ligation. We have identified a new, electron-deficient pyrazolone ligation and a regiospecific pyrazole ligation, both offering aqueous buffer stable and chemically inert products possessing triazole-like structures while not involving any heavy metal catalyst.
Topics: Catalysis; Electrons; Hydrazines; Hydrazones; Molecular Structure; Pyrazoles
PubMed: 32786214
DOI: 10.1021/acs.orglett.0c02545 -
European Journal of Medicinal Chemistry May 2014Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style.... (Review)
Review
Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review.
Topics: Animals; Anti-Obesity Agents; Dose-Response Relationship, Drug; Humans; Molecular Structure; Obesity; Prospective Studies; Pyrazoles; Receptor, Cannabinoid, CB1; Structure-Activity Relationship
PubMed: 24747288
DOI: 10.1016/j.ejmech.2014.04.011 -
Organic & Biomolecular Chemistry Sep 2019Rapamycin-induced dimerization of FKBP and FRB has been utilized as a tool for co-localizing two proteins of interest in numerous applications. Due to the tight binding...
Rapamycin-induced dimerization of FKBP and FRB has been utilized as a tool for co-localizing two proteins of interest in numerous applications. Due to the tight binding interaction of rapamycin with FKBP and FRB, the ternary complex formation is essentially irreversible. Since biological processes occur in a highly dynamic fashion with cycles of protein association and dissociation to generate a cellular response, it is useful to have chemical tools that function in a similar manner. We have developed arylazopyrazole-modified rapamycin analogs which undergo a configurational change upon light exposure and we observed enhanced ternary complex formation for the cis-isomer over the trans-isomer for one of the analogs.
Topics: Azo Compounds; HEK293 Cells; Humans; Light; Molecular Structure; Pyrazoles; Sirolimus; Stereoisomerism
PubMed: 31469140
DOI: 10.1039/c9ob01719d