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European Journal of Medicinal Chemistry Nov 2023The promising anti-angiogenetic properties of previously synthesized pyrazolyl ureas provided the rationale for the synthesis of novel 5-aminopyrazoles 2-5, differently...
The promising anti-angiogenetic properties of previously synthesized pyrazolyl ureas provided the rationale for the synthesis of novel 5-aminopyrazoles 2-5, differently decorated on the pyrazole nucleus. All the derivatives were tested by MTT assays and proved to be non-cytotoxic against eight different tumor cell lines and normal fibroblasts. An EdU proliferation assay was carried out on human foreskin fibroblasts and VEGF stimulated human umbilical vein endothelial cells which confirmed the absence of cytotoxicity of the compounds on human cells up to 20 μM concentration. To evaluate the influence of the newly synthesized pyrazoles on MAPK and PI3K signaling pathways, the phosphorylation of ERK1/2 and Akt was analyzed by Western blots from HFF and HUVEC cell lysates stimulated with growth factors in the presence or absence of the compounds. Pyrazoles 3b and 3c showed a significant inhibition of Akt phosphorylation in both tested cell lines with lower phosphorylation levels than the reference compound GeGe-3 in HUVEC. Furthermore, derivatives 2 and 3 appeared to strongly affect the migration of HFF cells in a wound healing assay, confirming their potential ability to interfere with the angiogenesis process. The new pyrazole library extends the structure-activity relationships of the previously isolated compounds and highlights the attractiveness of this chemical class for pathological cell migration and angiogenesis.
Topics: Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrazoles; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells
PubMed: 37597434
DOI: 10.1016/j.ejmech.2023.115727 -
International Journal of Molecular... Apr 2024Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound /HIT 8. We previously identified this molecule as a 'hit' during a high-throughput...
Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound /HIT 8. We previously identified this molecule as a 'hit' during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including , , and . The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.
Topics: Pyrazoles; Humans; Trypanosoma cruzi; Antiparasitic Agents; Drug Design; Leishmania infantum; Structure-Activity Relationship; Trypanosoma brucei rhodesiense; Antiprotozoal Agents
PubMed: 38731916
DOI: 10.3390/ijms25094693 -
Scientific Reports Jun 2020The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel...
The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel cascade reaction features an intramolecular N2-arylation of pyrazoles with allenes at the C-β position of triple bond. Screening in the colorectal cancer cell lines HCT116 and SW620 validated the feasibility of the methodology for generating bioactive compounds. The lead compound 7h which is active against HCT116 and SW620 with IC of 1.3 and 1.8 µM, respectively, can be synthesized and purified in a gram process synthetic scale in 7 hours. The mechanical studies indicated that compound 7h can induce cell cycle arrest in the G2/M phase and inhibit proliferation and viability in human colon cancer cells. Overall, compound 7h is represented as a promising starting point for the development of new anti-colorectal cancer drugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Humans; Pyrazines; Pyrazoles; Structure-Activity Relationship
PubMed: 32518332
DOI: 10.1038/s41598-020-66137-z -
Synthesis of Novel Pyrazole Derivatives Containing Phenylpyridine Moieties with Herbicidal Activity.Molecules (Basel, Switzerland) Sep 2022To discover new compounds with favorable herbicidal activity, a range of phenylpyridine moiety-containing pyrazole derivatives were designed, synthesized, and identified...
To discover new compounds with favorable herbicidal activity, a range of phenylpyridine moiety-containing pyrazole derivatives were designed, synthesized, and identified via NMR and HRMS. Their herbicidal activities against six species of weeds were evaluated in a greenhouse via both pre- and post-emergence treatments at 150 g a.i./hm. The bioassay revealed that a few compounds exhibited moderate herbicidal activities against , , and in post-emergence treatment. For instance, compounds and demonstrated 50% inhibition activity against , which was slightly superior to pyroxasulfone. Thus, compounds and may serve as the new possible leading compounds for the discovery of post-emergence herbicides.
Topics: Digitaria; Herbicides; Plant Weeds; Pyrazoles; Structure-Activity Relationship
PubMed: 36234814
DOI: 10.3390/molecules27196274 -
Molecules (Basel, Switzerland) Dec 2015With the objective of finding valuable herbicidal candidates, a series of new 5-heterocycloxy-3-methyl-1-substituted-1H-pyrazoles were synthesized and their herbicidal...
With the objective of finding valuable herbicidal candidates, a series of new 5-heterocycloxy-3-methyl-1-substituted-1H-pyrazoles were synthesized and their herbicidal activities were evaluated. The bioassay results showed that some compounds exhibited excellent herbicidal activities at the concentration of 100 mg/L, and compound 5-chloro-2-((3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)oxy)pyrimidine showed bleaching activity to green weeds. In greenhouse conditions, this compound also showed excellent post-emergence herbicidal effect against Digitaria sanguinalis L. at the dosage of 750 g a. i. ha(-1).
Topics: Herbicides; Molecular Structure; Plant Weeds; Pyrazoles; Structure-Activity Relationship
PubMed: 26712728
DOI: 10.3390/molecules21010039 -
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 -
Biomedicine & Pharmacotherapy =... Jul 2019Pyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we...
Pyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we report on research we have performed with the aim of continuing the biological evaluation of the regio-isomeric pyrazole compounds, LQFM-020 (fluorine, para position), LQFM-021 (fluorine, meta position), and LQFM-039 (fluorine, ortho position) in models of pain induced by acidified saline, capsaicin, and formalin. We also investigated the mechanisms of action of these compounds via electrophysiological analyses using the two-electrode voltage-clamp technique and heterologous expression in Xenopus laevis oocytes. This enabled us to study different potassium channel subtypes: the ASIC-1α channel, TRPV-1, and μMOR receptors. Our results indicate that LQFM-020, LQFM-021, and LQFM-039 (15, 30 or 60 mg.kg) compounds inhibited the nociceptive response induced by acidified saline in a dose-dependent manner. The dose of 30 mg.kg inhibited the nociceptive response induced by capsaicin by 53.3%, 51.4%, and 52.1%, respectively. In addition, we found that naloxone reverses the antinociceptive effect produced by the compounds in both phases of the formalin test. In electrophysiological analyses, we observed that the LQFM-020, LQFM-021, and LQFM-039 compounds did not modulate voltage-gated K + channel subtypes. In contrast, all the compounds tested inhibited the ASIC-1α channel at pH 4.5, with IC50-values of 96.1, 91.6, and 235.2 μM, respectively. All compounds also inhibited the TRPV-1 channel with IC50-values of 139.1, 212.5, and 159.1 μM, respectively. In contrast to the ASIC-1α and TRPV-1 targets, all compounds showed agonist activity on the μMOR receptor with an EC50-value of 117.4, 98.9, and 86.3 μM, respectively. We thus conclude that the ASIC-1α, TRPV-1, and μMOR channels are targets that are directly involved in the antinociceptive effect of LQFM-020, LQFM-021, and LQFM-039. Furthermore, the modifications of the fluorine positions in the phenyl analogs do not change the analgesic effect. However, LQFM-039 showed lower interaction with ASIC-1α channel.
Topics: Acid Sensing Ion Channels; Action Potentials; Analgesics; Animals; Male; Mice; Molecular Structure; Nociception; Oocytes; Pain Measurement; Patch-Clamp Techniques; Pyrazoles; Receptors, Opioid, mu; TRPV Cation Channels; Xenopus laevis
PubMed: 31055237
DOI: 10.1016/j.biopha.2019.108915 -
Cells Feb 2021Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women...
Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene-metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene-metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.
Topics: Cell Count; Cell Proliferation; Deoxyglucose; Estradiol; Estrogens; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Metabolic Networks and Pathways; Metabolome; Metabolomics; Nitriles; Oligomycins; Pyrazoles; Receptors, Estrogen; Transcriptome
PubMed: 33672651
DOI: 10.3390/cells10020455 -
Molecules (Basel, Switzerland) Oct 2021Microwave irradiation has become a popular heating technique in organic synthesis, mainly due to its short reaction times, solventless reactions, and, sometimes, higher... (Review)
Review
Microwave irradiation has become a popular heating technique in organic synthesis, mainly due to its short reaction times, solventless reactions, and, sometimes, higher yields. Additionally, microwave irradiation lowers energy consumption and, consequently, is ideal for optimization processes. Moreover, there is evidence that microwave irradiation can improve the regioselectivity and stereoselectivity aspects of vital importance in synthesizing bioactive compounds. These crucial features of microwave irradiation contribute to its inclusion in green chemistry procedures. Since 2003, the use of microwave-assisted organic synthesis has become common in our laboratory, making our group one of the first Portuguese research groups to implement this heating source in organic synthesis. Our achievements in the transformation of heterocyclic compounds, such as (/)-3-styryl-4-chromen-4-ones, ()-3-(2-hydroxyphenyl)-4-styryl-1-pyrazole, ()-2-(4-arylbut-1-en-3-yn-1-yl)-4-chromen-4-ones, or ()-2-[2-(5-aryl-2-methyl-2-1,2,3-triazol-4-yl)vinyl]-4-chromen-4-ones, will be discussed in this review, highlighting the benefits of microwave irradiation use in organic synthesis.
Topics: Chemistry, Pharmaceutical; Chromones; Combinatorial Chemistry Techniques; Enzyme Inhibitors; Heating; Humans; Microwaves; Molecular Structure; Pyrazoles; Quinolones
PubMed: 34684877
DOI: 10.3390/molecules26206293 -
Molecules (Basel, Switzerland) Sep 2023Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease's symptoms. So, drug...
Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease's symptoms. So, drug development for the management of osteoarthritis represents an important challenge in the medical field. This work is based on the development of a new benzofuran-pyrazole-pyridine-based compound with potential anti-inflammatory and anti-osteoarthritis properties. Microanalytical and spectral data confirmed the chemical structure of compound . The biological assays indicated that compound produces multifunctional activity as an anti-osteoarthritic candidate via inhibition of pro-inflammatory mediators, including RANTES, CRP, COMP, CK, and LPO in OA rats. Histopathological and pharmacokinetic studies confirmed the safety profile of the latter molecule. Accordingly, compound is considered a promising anti-osteoarthritis agent and deserves deeper investigation in future trials.
Topics: Humans; Rats; Animals; Osteoarthritis; Anti-Inflammatory Agents; Pyrazoles; Benzofurans; Pyridines
PubMed: 37836657
DOI: 10.3390/molecules28196814