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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 -
Biomolecules Dec 2022The combination of two compounds with known antimicrobial activity may, in some cases, be an effective way to limit the resistance to antibiotics of specific pathogens....
The combination of two compounds with known antimicrobial activity may, in some cases, be an effective way to limit the resistance to antibiotics of specific pathogens. Molecules carrying pyrazole moiety are well known for their bioactive properties and have wide applicability in the medical and pharmaceutical field. Surfactants have, among other useful properties, the ability to affect the growth of microorganisms. The paper reports on the effect of the combination of two pyrazole derivatives, (1H-pyrazol-1-yl) methanol 1-hydroxymethylpyrazole (SAM1) and 1,1'methandiylbis (1H-pyrazol) (AM1), with sorbitan monolaurate (polysorbate 21, Tween 21, T21) on the growth of Gram-positive and Gram-negative bacteria. The results demonstrated a different ability of this combination to inhibit and . T21 intensified the inhibitory activity of the pyrazoles to a greater extent in the Gram-negative bacteria compared to the Gram-positive ones, a fact confirmed by time-kill experiments. The experimental data showed that the association of T21 with the pyrazoles led to the increased release of intracellular material and a more intense uptake of crystal violet, which indicates that the potentiation of the antibacterial effect was based on the modification of the normal permeability of bacterial cells. T21 acted as a modulating factor and increased the permeability of the membrane, allowing the accelerated penetration of the pyrazoles inside the bacterial cells. This fact is important in controlling the global increase in microbial resistance to antibiotics and antimicrobials and finding viable solutions to overcome the antibiotic crisis. The paper highlights the possibility of using non-toxic surfactant molecules in antimicrobial combinations with practical applications. This could widen the range of adjuvants in applications which would be useful in the control of resistant microorganisms.
Topics: Anti-Bacterial Agents; Polysorbates; Gram-Negative Bacteria; Gram-Positive Bacteria; Anti-Infective Agents; Pyrazoles; Surface-Active Agents; Microbial Sensitivity Tests
PubMed: 36551246
DOI: 10.3390/biom12121819 -
Bioorganic Chemistry Dec 2021A new series of N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives 11a-o were designed and synthesized based on our previous works. The new series...
A new series of N-(2-((4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine sulfonamide derivatives 11a-o were designed and synthesized based on our previous works. The new series was tested for its anticancer and anti-inflammatory effects. The anticancer profile of final target compounds was obtained by testing them over 60 cell lines belong to nine types of cancers. Compound 11c showed the highest percent inhibition, so its potency was measured over the most sensitive cell line to determine its IC over each cell. In addition, compound 11c was tested over kinase panel to get its biological target(s). Compound 11c had strong activity over JNK1, JNK2, p38a and V600EBRAF. All final target compounds were tested against the four kinases to build a structure activity relationship. Compound 11c was subjected to cell cycle analysis to check at which phase is affected by 11c. The anti-inflammatory effect of final target compounds was screened by testing their ability to inhibit both nitric oxide release and prostaglandin E2 production on raw 264.7 macrophages in addition to test their cytotoxic effect on the same cells. Compound 11n showed the highest ability to inhibit prostaglandin E2 and all compound showed moderate to low activity regarding inhibition of nitric oxide release. Compound 11n was investigated for its ability to reduce Interleukin 6 and TNF-alpha. In addition, compound 11n was tested for its effect on induced Nitric oxide synthase (iNOS), and COX-2 mRNA expression level and its effect on nitric oxide synthase (iNOS), COX-1 and COX-2 protein levels where it showed selectivity for COX-2 compared to COX-1 and iNOS.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mice; Molecular Structure; Pyrazoles; Pyridines; RAW 264.7 Cells; Structure-Activity Relationship; Sulfonamides
PubMed: 34678604
DOI: 10.1016/j.bioorg.2021.105424 -
Medicinal Chemistry (Shariqah (United... 2022Pyrazole is a bioactive heterocyclic congener with numerous biological and pharmacological functionalities. Due to their multiple prospective applications, developing...
BACKGROUND
Pyrazole is a bioactive heterocyclic congener with numerous biological and pharmacological functionalities. Due to their multiple prospective applications, developing innovative and novel pyrazoles and analogs, revealing revolutionary methods for synthesizing this nucleus, investigating diverse potencies of that heterocycle, and exploring possible pyrazole applications are becoming increasingly relevant.
OBJECTIVES
Pyrazole scaffolds have been proven successful as antimicrobial, anticancer, and antimalarial therapeutics against multiple targets like DNA gyrase, topoisomerase IV, Hsp90, and several kinase enzymes. For this variability in the biotic zone, their moiety has gained the attention of many scientists interested in researching chemical and pharmacological profiles.
RESULTS
The review covers pyrazole scaffolds with a variety of biological functions and attempts to connect the structure-activity relationship. Multiple pyrazole analogs have been produced as lead compounds, and their activities have been evaluated.
CONCLUSION
The combination of pyrazole with other pharmacophores in a molecule might lead to novel potent therapeutic medicines, which could aid in the development of potent lead compounds.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antineoplastic Agents; Pyrazoles; Structure-Activity Relationship
PubMed: 35240964
DOI: 10.2174/1573406418666220303150640 -
Future Medicinal Chemistry Aug 2019Everyday studies prove the increasing need for newer and safer agents to control cellular inflammatory response, an underlying cause for the pathophysiology of many...
Everyday studies prove the increasing need for newer and safer agents to control cellular inflammatory response, an underlying cause for the pathophysiology of many other clinical cases. Two newly designed sets of schiff and chlacone substituted pyrazoles were synthesized and evaluated for their anti-inflammatory activities. Most potent representatives were chosen for investigation of ulcerogenic and molecular docking properties The synthesized compounds showed considerable edema inhibition percentage range if compared with celecoxib (13-93% and 58-93%, respectively) at different time intervals. Compound showed the best screening results if compared with celecoxib (inhibition % = 93.62 and 93.51% at 5 h, COX-1/COX-2 selectivity index SI = 215.44 and 308.16 and ulcer index = 7.25 and 8, respectively).
Topics: Animals; Anti-Inflammatory Agents; Binding Sites; Catalytic Domain; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Edema; Hydrogen Bonding; Male; Molecular Docking Simulation; Pyrazoles; Rats; Rats, Wistar; Structure-Activity Relationship
PubMed: 31517535
DOI: 10.4155/fmc-2018-0548 -
Bioorganic Chemistry Nov 2021Novel diarylpyrazole (5a-d, 6a-e, 12, 13, 14, 15a-c and 11a-g) derivatives were designed, synthesized and evaluated for their dual COX-2/sEH inhibitory activities via...
Novel diarylpyrazole (5a-d, 6a-e, 12, 13, 14, 15a-c and 11a-g) derivatives were designed, synthesized and evaluated for their dual COX-2/sEH inhibitory activities via recombinant enzyme assays to explore their anti-inflammatory activities and cardiovascular safety profiles. Comprehensively, the structures of the synthesized compounds were established via spectral and elemental analyses, followed by the assessment of both their in vitro COX inhibitory and in vivo anti-inflammatory activities. The most active compounds as COX inhibitors were further evaluated for their in vitro 5-LOX and sEH inhibitory activities, alongside with their in vivo analgesic and ulcerogenic effects. Compounds 6d and 11f showed excellent inhibitory activities against both COX-2 and sEH (COX-2 IC = 0.043 and 0.048 µM; sEH IC = 83.58 and 83.52 μM, respectively). Moreover, the compounds demonstrated promising results as anti-inflammatory and analgesic agents with considerable ED values and gastric safety profiles. Remarkably, the most active COX inhibitors 6d and 11f possessed improved cardiovascular safety profiles, if compared to celecoxib, as shown by the laboratory evaluation of both essential cardiac biochemical parameters (troponin-1, prostacyclin, tumor necrosis factor-α, lactate dehydrogenase, reduced glutathione and creatine kinase-M) and histopathological studies. On the other hand, docking simulations confirmed that the newly synthesized compounds displayed sufficient structural features required for binding to the target COX-2 and sEH enzymes. Also, in silico ADME studies prediction and drug-like properties of the compounds revealed favorable oral bioavailability results. Collectively, the present work could be featured as a promising future approach towards novel selective COX-2 inhibitors with declined cardiovascular risks.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Cardiovascular System; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Lipoxygenase Inhibitors; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 34619468
DOI: 10.1016/j.bioorg.2021.105394 -
Molecular Diversity Feb 2021A library of pyrazole-thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier-Haack reaction. The compounds were tested...
A library of pyrazole-thiazolidinone conjugates was synthesized using a molecular hybridization approach through a Vilsmeier-Haack reaction. The compounds were tested for anti-microbial activity against two Gram-positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus) and four Gram-negative bacteria (Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa). Among the compounds tested, 3-((2,4-dichlorophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-yl)methylene)hydrazinecarbothioamide (3a) and 2-((3-(2-chlorophenyl)-1-(2,4 dinitrophenyl)-1H-pyrazol-4-yl)methyleneamino)thiazolidin-4-one (4b) emerged as the most potent anti-microbial compounds with minimum bactericidal concentrations of < 0.2 µM against MRSA and S. aureus. Structure-activity relationship analysis further revealed that the presence of 2,4-dichloro moiety surprisingly influenced the activity of the compounds. Molecular docking studies of the compounds into the crystal structure of topoisomerase II and topoisomerase IV suggest that compounds 3a and 4b preferably interact with the targets through hydrogen bonding.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Hydrazines; Microbial Sensitivity Tests; Molecular Docking Simulation; Pyrazoles; Structure-Activity Relationship; Thioamides; Thiosemicarbazones
PubMed: 32086698
DOI: 10.1007/s11030-020-10046-w -
Chemistry & Biodiversity Aug 2023In this study, we designed and synthesized 19 nitrogen-containing heterocyclic derivatives of panaxadiol (PD). We first reported the antiproliferative activity of these...
In this study, we designed and synthesized 19 nitrogen-containing heterocyclic derivatives of panaxadiol (PD). We first reported the antiproliferative activity of these compounds against four different tumor cells. The results of the MTT assay showed that the PD pyrazole derivative (compound 12b) had the best antitumor activity and could significantly inhibit the proliferation of four tested tumor cells. For A549 cells, the IC value was as low as 13.44±1.23 μM. Western blot analysis showed that the PD pyrazole derivative was a bifunctional regulator. On the one hand, it can down-regulate the expression of HIF-1α by acting on PI3 K/AKT signaling pathway in A549 cells. On the other hand, it can induce the decrease of CDKs protein family and E2F1 protein expression levels, thus playing a crucial role in cell cycle arrest. According to the results of molecular docking, we found that multiple hydrogen bonds were formed between the PD pyrazole derivative and two related proteins, and the docking score of the derivative was also significantly higher than that of the crude drug. In summary, the study of the PD pyrazole derivative laid a foundation for the development of ginsenoside as an antitumor agent.
Topics: Structure-Activity Relationship; Ginsenosides; Cell Line, Tumor; Molecular Docking Simulation; Cell Proliferation; Antineoplastic Agents; Pyrazoles; Drug Screening Assays, Antitumor; Molecular Structure; Apoptosis
PubMed: 37279052
DOI: 10.1002/cbdv.202300507 -
European Journal of Medicinal Chemistry Apr 2020Transforming growth factor-β (TGF-β) is a member of a superfamily of pleiotropic proteins that regulate multiple cellular processes such as growth, development and... (Review)
Review
Transforming growth factor-β (TGF-β) is a member of a superfamily of pleiotropic proteins that regulate multiple cellular processes such as growth, development and differentiation. Following binding to type I and II TGF-β serine/threonine kinase receptors, TGF-β activates downstream signaling cascades involving both SMAD-dependent and -independent pathways. Aberrant TGF-β signaling is associated with a variety of diseases, such as fibrosis, cardiovascular disease and cancer. Hence, the TGF-β signaling pathway is recognized as a potential drug target. Various organic molecules have been designed and developed as TGF-β signaling pathway inhibitors and they function by either down-regulating the expression of TGF-β or by inhibiting the kinase activities of the TGF-β receptors. In this review, we discuss the current status of research regarding organic molecules as TGF-β inhibitors, focusing on the biological functions and the binding poses of compounds that are in the market or in the clinical or pre-clinical phases of development.
Topics: Animals; Drug Development; Humans; Ligands; Molecular Structure; Pyrazoles; Receptors, Transforming Growth Factor beta; Small Molecule Libraries; Transforming Growth Factor beta
PubMed: 32092587
DOI: 10.1016/j.ejmech.2020.112154 -
Chemical Research in Toxicology Aug 2021Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of...
Cytochrome P450 2C8 (CYP2C8) is a major drug-metabolizing enzyme in humans and is responsible for the metabolism of ∼5% drugs in clinical use. Thus, inhibition of CYP2C8, which causes potential adverse drug events, cannot be neglected. The in vitro drug interaction studies guidelines for industry issued by the FDA also point out that it needs to be determined whether investigated drugs are CYP2C8 inhibitors before clinical trials. However, current studies mainly focus on predicting the inhibitors of other major P450 enzymes, and the importance of CYP2C8 inhibition has been overlooked. Therefore, there is a need to develop models for identifying potential CYP2C8 inhibition. In this study, in silico classification models for predicting CYP2C8 inhibition were built by five machine-learning methods combined with nine molecular fingerprints. The performance of the models built was evaluated by test and external validation sets. The best model had AUC values of 0.85 and 0.90 for the test and external validation sets, respectively. The applicability domain was analyzed based on the molecular similarity and exhibited an impact on the improvement of prediction accuracy. Furthermore, several representative privileged substructures such as 1-benzo[]imidazole, 1-phenyl-1-pyrazole, and quinoline were identified by information gain and substructure frequency analysis. Overall, our results would be helpful for the prediction of CYP2C8 inhibition.
Topics: Computer Simulation; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Drug Discovery; Humans; Imidazoles; Machine Learning; Molecular Docking Simulation; Pyrazoles
PubMed: 34255486
DOI: 10.1021/acs.chemrestox.1c00078