-
Molecules (Basel, Switzerland) Dec 2022Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile,... (Review)
Review
Pyrazole, an important pharmacophore and a privileged scaffold of immense significance, is a five-membered heterocyclic moiety with an extensive therapeutic profile, viz., anti-inflammatory, anti-microbial, anti-anxiety, anticancer, analgesic, antipyretic, etc. Due to the expansion of pyrazolecent red pharmacological molecules at a quicker pace, there is an urgent need to put emphasis on recent literature with hitherto available information to recognize the status of this scaffold for pharmaceutical research. The reported potential pyrazole-containing compounds are highlighted in the manuscript for the treatment of cancer and inflammation, and the results are mentioned in % inhibition of inflammation, % growth inhibition, IC, etc. Pyrazole is an important heterocyclic moiety with a strong pharmacological profile, which may act as an important pharmacophore for the drug discovery process. In the struggle to cultivate suitable anti-inflammatory and anticancer agents, chemists have now focused on pyrazole biomolecules. This review conceals the recent expansion of pyrazole biomolecules as anti-inflammatory and anticancer agents with an aim to provide better correlation among different research going around the world.
Topics: Humans; Anti-Inflammatory Agents; Drug Design; Pyrazoles; Antineoplastic Agents; Inflammation; Structure-Activity Relationship; Neoplasms
PubMed: 36557840
DOI: 10.3390/molecules27248708 -
Scientific Reports Apr 2023Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules...
Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.
Topics: Female; Humans; Breast Neoplasms; Cell Cycle Checkpoints; Apoptosis; Caspases; Antineoplastic Agents; MCF-7 Cells; Reactive Oxygen Species; Pyrazoles; Pyridines; Naphthyridines; Cell Proliferation; Cell Line, Tumor
PubMed: 37005457
DOI: 10.1038/s41598-023-32489-5 -
Scientific Reports May 2023Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective,...
Catalpol, a natural product mainly existed in plenty of Chinese traditional medicines, is an iridoid compound with the comprehensive effects on neuroprotective, anti-inflammatory, choleretic, hypoglycemic and anticancer. However, there are some disadvantages for catalpol such as a short half-life in vivo, low druggability, stingy binding efficiency to target proteins and so on. It is necessary to make structural modification and optimization which enhance its performance on disease treatments and clinic applications. Pyrazole compounds have been reported to have excellent anticancer activities. Based on the previous research foundation of our research group on iridoids and the anticancer activities of catalpol and pyrazole, a series of pyrazole modified catalpol compounds were synthesized by principle of drug combination for serving as potential cancer inhibitors. These derivatives are characterized by H NMR, C NMR and HRMS. The efficacy of anti-esophageal cancer and anti-pancreatic cancer activities were evaluated by the MTT assay on two esophageal cancer cells Eca-109 and EC-9706, and two pancreatic cancer cells PANC-1, BxPC-3 and normal pancreatic cell line HPDE6-C7, which showed that the compound 3e had strong inhibitory activity against esophageal cancer cells, this providing a theoretical basis for the discovery of catalpol-containing drugs.
Topics: Humans; Iridoid Glucosides; Neoplasms; Cell Line; Pyrazoles
PubMed: 37173367
DOI: 10.1038/s41598-023-33403-9 -
Drugs May 2019Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan and Korea and is being... (Review)
Review
Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan and Korea and is being researched in several countries. Teneligliptin is a potent, selective, and long-lasting DPP-4 inhibitor with a t of approximately 24 h and unique pharmacokinetic properties: it is metabolized by cytochrome P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3), or excreted from the kidney in an unchanged form. Because of its multiple elimination pathways, dose adjustment is not needed in patients with hepatic or renal impairment, and it is considered to have a low potential for drug-drug interactions. Clinical studies and postmarketing surveillance show that teneligliptin, administered as monotherapy and/or in combination with antihyperglycemic agents, is effective and well tolerated in T2DM patients, including in elderly patients and those with renal impairment. Furthermore, teneligliptin has antioxidative properties, which induce the antioxidant cascade, as well as ·OH scavenging properties. In addition, it has shown endothelial protective effects in several non-clinical and clinical studies. From its unique profile and clinical data, teneligliptin represents a potential therapeutic option in a wide variety of patients, including elderly diabetic patients and those with renal impairment. The fixed-dose combination (FDC) tablet of teneligliptin and canagliflozin has been approved in Japan; this is the first FDC tablet of a DPP-4 inhibitor and sodium glucose co-transporter 2 inhibitor in Japan, and the third globally. The FDC tablet may also provide additional prescribing and adherence benefits.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Canagliflozin; Child; Child, Preschool; Cytochrome P-450 CYP3A; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Drug Interactions; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Infant; Infant, Newborn; Japan; Male; Middle Aged; Oxygenases; Pyrazoles; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidines
PubMed: 30982160
DOI: 10.1007/s40265-019-01086-0 -
Molecules (Basel, Switzerland) Jul 2020Nitrated-pyrazole-based energetic compounds have attracted wide publicity in the field of energetic materials (EMs) due to their high heat of formation, high density,... (Review)
Review
Nitrated-pyrazole-based energetic compounds have attracted wide publicity in the field of energetic materials (EMs) due to their high heat of formation, high density, tailored thermal stability, and detonation performance. Many nitrated-pyrazole-based energetic compounds have been developed to meet the increasing demands of high power, low sensitivity, and eco-friendly environment, and they have good applications in explosives, propellants, and pyrotechnics. Continuous and growing efforts have been committed to promote the rapid development of nitrated-pyrazole-based EMs in the last decade, especially through large amounts of Chinese research. Some of the ultimate aims of nitrated-pyrazole-based materials are to develop potential candidates of castable explosives, explore novel insensitive high energy materials, search for low cost synthesis strategies, high efficiency, and green environmental protection, and further widen the applications of EMs. This review article aims to present the recent processes in the synthesis and physical and explosive performances of the nitrated-pyrazole-based Ems, including monopyrazoles with nitro, bispyrazoles with nitro, nitropyrazolo[4,3-]pyrazoles, and their derivatives, and to comb the development trend of these compounds. This review intends to prompt fresh concepts for designing prominent high-performance nitropyrazole-based EMs.
Topics: Explosive Agents; Nitrates; Nitro Compounds; Pyrazoles; Thermodynamics
PubMed: 32751631
DOI: 10.3390/molecules25153475 -
Future Oncology (London, England) 2015The JAK1 and JAK2 inhibitor ruxolitinib has approved indications in myelofibrosis, a BCR-AB1-negative myeloproliferative neoplasm associated with progressive bone marrow... (Review)
Review
The JAK1 and JAK2 inhibitor ruxolitinib has approved indications in myelofibrosis, a BCR-AB1-negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis and shortened survival. In Phase III clinical studies, ruxolitinib provided rapid and durable improvement of myelofibrosis-related splenomegaly and symptoms irrespective of mutation status, and was associated with a survival advantage compared with placebo or best available therapy. Because of dose-dependent cytopenias, blood count monitoring and dose titration are important to optimize therapy. Specific precautions apply to the treatment of patients with or at risk of serious infections. Discontinuation of ruxolitinib generally leads to symptom return within 1 week. Ruxolitinib also is approved for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Janus Kinases; Nitriles; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 25757677
DOI: 10.2217/fon.14.272 -
Molecules (Basel, Switzerland) Mar 2023Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes....
Glycogen phosphorylase (GP) is a key regulator of glucose levels and, with that, an important target for the discovery of novel treatments against type 2 diabetes. β-d-Glucopyranosyl derivatives have provided some of the most potent GP inhibitors discovered to date. In this regard, -β-d-glucopyranosyl azole type inhibitors proved to be particularly effective, with 2- and 4-β-d-glucopyranosyl imidazoles among the most potent designed to date. His377 backbone C=O hydrogen bonding and ion-ion interactions of the protonated imidazole with Asp283 from the 280s loop, stabilizing the inactive state, were proposed as crucial to the observed potencies. Towards further exploring these features, 4-amino-3-(β-d-glucopyranosyl)-5-phenyl-1-pyrazole () and 3-(β-d-glucopyranosyl)-4-guanidino-5-phenyl-1-pyrazole () were designed and synthesized with the potential to exploit similar interactions. Binding assay experiments against rabbit muscle GPb revealed as a moderate inhibitor (IC = 565 µM), but displayed no inhibition at 625 µM concentration. Towards understanding the observed inhibitions, docking and post-docking molecular mechanics-generalized Born surface area (MM-GBSA) binding free energy calculations were performed, together with Monte Carlo and density functional theory (DFT) calculations on the free unbound ligands. The computations revealed that while was predicted to hydrogen bond with His377 C=O in its favoured tautomeric state, the interactions with Asp283 were not direct and there were no ion-ion interactions; for , the most stable tautomer did not have the His377 backbone C=O interaction and while ion-ion interactions and direct hydrogen bonding with Asp283 were predicted, the conformational strain and entropy loss of the ligand in the bound state was significant. The importance of consideration of tautomeric states and ligand strain for glucose analogues in the confined space of the catalytic site with the 280s loop in the closed position was highlighted.
Topics: Pyrazoles; Glycogen Phosphorylase; Density Functional Theory; Molecular Docking Simulation; Monte Carlo Method; Molecular Conformation; Glucose; Diabetes Mellitus, Type 2
PubMed: 37049768
DOI: 10.3390/molecules28073005 -
Molecules (Basel, Switzerland) Apr 2021Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include... (Review)
Review
Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB and/or CB receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB or CB receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.
Topics: Cannabinoids; Molecular Structure; Protein Binding; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship
PubMed: 33917187
DOI: 10.3390/molecules26082126 -
International Journal of Molecular... Apr 2024Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously...
Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives - were evaluated in in vitro assays. Derivative showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and -acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.
Topics: Humans; Pyrazoles; Hydrazones; Antioxidants; Structure-Activity Relationship; Antineoplastic Agents; Cell Proliferation; Amides; Cell Line, Tumor; Reactive Oxygen Species; MCF-7 Cells; HeLa Cells
PubMed: 38731825
DOI: 10.3390/ijms25094607 -
Molecules (Basel, Switzerland) Jul 2022Pyrazole and its derivatives are considered a privileged -heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy... (Review)
Review
Pyrazole and its derivatives are considered a privileged -heterocycle with immense therapeutic potential. Over the last few decades, the pot, atom, and step economy (PASE) synthesis of pyrazole derivatives by multicomponent reactions (MCRs) has gained increasing popularity in pharmaceutical and medicinal chemistry. The present review summarizes the recent developments of multicomponent reactions for the synthesis of biologically active molecules containing the pyrazole moiety. Particularly, it covers the articles published from 2015 to date related to antibacterial, anticancer, antifungal, antioxidant, α-glucosidase and α-amylase inhibitory, anti-inflammatory, antimycobacterial, antimalarial, and miscellaneous activities of pyrazole derivatives obtained exclusively via an MCR. The reported analytical and activity data, plausible synthetic mechanisms, and molecular docking simulations are organized in concise tables, schemes, and figures to facilitate comparison and underscore the key points of this review. We hope that this review will be helpful in the quest for developing more biologically active molecules and marketed drugs containing the pyrazole moiety.
Topics: Anti-Bacterial Agents; Antifungal Agents; Chemistry, Pharmaceutical; Molecular Docking Simulation; Pyrazoles; alpha-Glucosidases
PubMed: 35897899
DOI: 10.3390/molecules27154723