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ChemMedChem Sep 2021Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed...
Pyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5-0.25) and minimum adjunctive concentration (MAC=128-32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our "in house" permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram-negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram-negative antibacterials.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Dose-Response Relationship, Drug; Meropenem; Microbial Sensitivity Tests; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazoles
PubMed: 34096189
DOI: 10.1002/cmdc.202100321 -
Anti-cancer Agents in Medicinal... 2022The study aims to synthesize hybrid molecules containing pyrazole and aryldiazenyl/arylhydrazono fragments with promising anticancer activity.
AIMS
The study aims to synthesize hybrid molecules containing pyrazole and aryldiazenyl/arylhydrazono fragments with promising anticancer activity.
BACKGROUND
The clinical effectiveness of anticancer drugs is limited by their adverse side effects and patient resistance. Therefore, the development of safer classes of drugs through rational drug design is imperative.
OBJECTIVE
Considering the anticancer potential of the pyrazole moiety, the study was carried out with the objective of synthesizing some hybrid pyrazole derivatives with anticancer potential.
METHODS
The anticancer potential of these pyrazolyl analogues were evaluated by sulforhodamine B assay using three cancer cell lines MCF-7, HepG2, and HCT-116.
RESULTS
HCT-116 was the most sensitive cell line against these pyrazolyl analogues. Among these newly synthesised derivatives, 1-(4-((4-bromophenyl)diazenyl)-3,5-dimethyl-1H-pyrazol-1-yl)-2-(naphthalen-2-yloxy)ethan-1-one (5e) emerged as a promising anticancer agent (IC 3.6-24.6 μM), having a xanthine oxidase inhibitory effect (IC 10.87 μM). To obtain further insights into the binding interactions of these molecules, molecular docking studies were also carried out.
CONCLUSION
In summary, our findings suggest that these hybrid pyrazolyl derivatives can be considered as potential lead molecules for anticancer agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Xanthine Oxidase
PubMed: 35016597
DOI: 10.2174/1871520622666220110162651 -
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 -
Bioorganic & Medicinal Chemistry Feb 2020The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly...
The apelinergic system comprises the apelin receptor and its cognate apelin and elabela peptide ligands of various lengths. This system has become an increasingly attractive target for pulmonary and cardiometabolic diseases. Small molecule regulators of this receptor with good drug-like properties are needed. Recently, we discovered a novel pyrazole based small molecule agonist 8 of the apelin receptor (EC = 21.5 µM, K = 5.2 µM) through focused screening which was further optimized to initial lead 9 (EC = 0.800 µM, K = 1.3 µM). In our efforts to synthesize more potent agonists and to explore the structural features important for apelin receptor agonism, we carried out structural modifications at N1 of the pyrazole core as well as the amino acid side-chain of 9. Systematic modifications at these two positions provided potent small molecule agonists exhibiting EC values of <100 nM. Recruitment of β-arrestin as a measure of desensitization potential of select compounds was also investigated. Functional selectivity was a feature of several compounds with a bias towards calcium mobilization over β-arrestin recruitment. These compounds may be suitable as tools for in vivo studies of apelin receptor function.
Topics: Animals; Apelin Receptors; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Humans; Microsomes, Liver; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 31948845
DOI: 10.1016/j.bmc.2019.115237 -
European Journal of Medicinal Chemistry May 2016The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the... (Review)
Review
The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.
Topics: Chemistry, Pharmaceutical; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Thiazolidines
PubMed: 26922234
DOI: 10.1016/j.ejmech.2016.02.030 -
Bioorganic & Medicinal Chemistry Letters Sep 2017A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1...
A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with K=0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
Topics: Dose-Response Relationship, Drug; Humans; Mesylates; Models, Molecular; Molecular Structure; Phenylpropionates; Pyrazoles; Structure-Activity Relationship; TRPV Cation Channels
PubMed: 28838698
DOI: 10.1016/j.bmcl.2017.08.020 -
ChemMedChem Dec 2018The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated...
The mitogen-activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B-Raf . New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B-Raf inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}-N-[1-(4-methoxyphenyl)-1H-pyrazol-4-yl]benzamide was the most potent agent with IC values of 0.035±0.004 μm (B-Raf kinase) and 0.39±0.04 μm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B-Raf inhibitor candidates.
Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Cell Line, Tumor; Drug Design; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles
PubMed: 30353975
DOI: 10.1002/cmdc.201800574 -
European Journal of Medicinal Chemistry Jan 20061H-pyrazole-4-carbohydrazides were synthesized and their leishmanicidal in vitro activities and cytotoxic effects were investigated. The drugs prototypes of these new...
1H-pyrazole-4-carbohydrazides were synthesized and their leishmanicidal in vitro activities and cytotoxic effects were investigated. The drugs prototypes of these new compounds (ketoconazole, benznidazole, allopurinol and pentamidine) were also tested. It was found that among all the 1H-pyrazole-4-carbohydrazides derivatives examined, the most active compounds were those with X = Br, Y = NO2 (27) and X = NO2, Y = Cl (15) derivatives which showed to be most effective on promastigotes forms of L. amazonensis than on L. chagasi and L. braziliensis species. When tested against murine peritoneal macrophages as mammalian host cell controls of toxicity, 1-(4-Br-phenyl)-N'-[(4-NO(2)-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (27) (EC50 = 50 microM l(-1)) and 1-(4-NO2-phenyl)-N'-[(4-Cl-phenyl)methylene]-1H-pyrazole-4-carbohydrazides (15) EC50 = 80 microM l(-1))] was reasonably toxic. However, both compounds were less toxic than pentamidine and ketoconazole. These results provide new perspectives on the development of drugs with activities against Leishmania parasite.
Topics: Animals; Antiprotozoal Agents; Cell Survival; Cells, Cultured; Drug Evaluation, Preclinical; Hydrazines; Leishmania; Leishmaniasis; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Molecular Structure; Parasitic Sensitivity Tests; Pyrazoles; Structure-Activity Relationship
PubMed: 16300859
DOI: 10.1016/j.ejmech.2005.10.007 -
Bioorganic & Medicinal Chemistry Letters Oct 2007A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1...
A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.
Topics: Administration, Oral; Animals; Checkpoint Kinase 1; Cyanides; Hydrogen; Indenes; Inhibitory Concentration 50; Mice; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyridines; Rats; Structure-Activity Relationship
PubMed: 17768051
DOI: 10.1016/j.bmcl.2007.07.069 -
European Journal of Medicinal Chemistry Oct 2014Condensed pyrazole derivatives are important heterocyclic compounds due to their excellent biological activities and have been widely applied in pharmaceutical and... (Review)
Review
Condensed pyrazole derivatives are important heterocyclic compounds due to their excellent biological activities and have been widely applied in pharmaceutical and agromedical fields. In recent years, numerous condensed pyrazole derivatives have been synthesized and advanced to clinic studies with various biological activities. In this review, we summarized the reported synthesis methods of condensed pyrazole derivatives from 2010 until now. All compounds are divided into three parts according to the rings connected to pyrazole-ring, i.e. [5, 5], [5,F 6], and [5, 7]-condensed pyrazole derivatives. The biological activities and applications in pharmaceutical fields are briefly introduced to offer an orientation for the design and synthesis of condensed pyrazole derivatives with good biological activities.
Topics: Chemistry Techniques, Synthetic; Drug Design; Humans; Pyrazoles
PubMed: 25104650
DOI: 10.1016/j.ejmech.2014.07.102