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Molecules (Basel, Switzerland) Mar 2020The present work aims to design and synthesize novel series of spiro pyrazole-3,3'-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial...
The present work aims to design and synthesize novel series of spiro pyrazole-3,3'-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC values obtained were 5.7-21.3 and 5.8-37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h the highest cytotoxicity with IC value of 19.2µg/mL relative to doxorubicin (IC = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.
Topics: Antineoplastic Agents; Apoptosis; HCT116 Cells; Hep G2 Cells; Humans; MCF-7 Cells; Oxindoles; Pyrazoles; Structure-Activity Relationship
PubMed: 32138244
DOI: 10.3390/molecules25051124 -
Molecules (Basel, Switzerland) Dec 2022A general approach towards the synthesis of tetrahydro-4-pyrazolo[1,5-][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-]indol-1-one and...
A general approach towards the synthesis of tetrahydro-4-pyrazolo[1,5-][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-]indol-1-one and tetrahydro-1-benzo[4,5]imidazo[1,2-][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation-yielding target pyrazolo[1,5-][1,4]diazepin-4-ones. A straightforward two-step synthetic approach was applied to expand the current study and successfully functionalize ethyl 1-indole- and ethyl 1-benzo[]imidazole-2-carboxylates. The structures of fused heterocyclic compounds were confirmed by H, C, and N-NMR spectroscopy and HRMS investigation.
Topics: Pyrazoles; Cyclization
PubMed: 36557800
DOI: 10.3390/molecules27248666 -
Molecules (Basel, Switzerland) Jan 2023In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that...
In our initial publication on the in vitro testing of more than 200 compounds, we demonstrated that small molecules can inhibit phagocytosis. We therefore theorized that a small molecule drug discovery-based approach to the treatment of immune cytopenias (ITP, AIHA, HTR, DHTR) is feasible. Those earlier studies showed that small molecules with anti-phagocytic groups, such as the pyrazole core, are good models for producing efficacious phagocytosis inhibitors with low toxicity. We recently screened a chemical library of 80 compounds containing pyrazole/isoxazole/pyrrole core structures and found four hit molecules for further follow-up, all having the pyrazole core structure. Subsequent evaluation via MTT viability, LDH release, and apoptosis, led to the selection of two lead compounds with negligible toxicity and high efficacy. In an in vitro assay for inhibition of phagocytosis, their IC values were 2-4 µM. The rational development of these discoveries from hit to lead molecule stage, viz. independent synthesis/scale up of hit molecules, and in vivo activities in mouse models of autoimmune disease, will result in the selection of a lead compound(s) for further pre-clinical evaluation.
Topics: Mice; Animals; Phagocytosis; Drug Discovery; Pyrazoles; Structure-Activity Relationship
PubMed: 36677815
DOI: 10.3390/molecules28020757 -
Molecules (Basel, Switzerland) Feb 2020Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the...
Several anti-inflammatory agents based on pyrazole and imidazopyrazole scaffolds and a large library of substituted catechol PDE4D inhibitors were reported by us in the recent past. To obtain new molecules potentially able to act on different targets involved in inflammation onset we designed and synthesized a series of hybrid compounds by linking pyrazole and imidazo-pyrazole scaffolds to differently decorated catechol moieties through an acylhydrazone chain. Some compounds showed antioxidant activity, inhibiting reactive oxygen species (ROS) elevation in neutrophils, and a good inhibition of phosphodiesterases type 4D and, particularly, type 4B, the isoform most involved in inflammation. In addition, most compounds inhibited ROS production also in platelets, confirming their ability to exert an antiinflammatory response by two independent mechanism. Structure-activity relationship (SAR) analyses evidenced that both heterocyclic scaffolds (pyrazole and imidazopyrazole) and the substituted catechol moiety were determinant for the pharmacodynamic properties, even if hybrid molecules bearing to the pyrazole series were more active than the imidazopyrazole ones. In addition, the pivotal role of the catechol substituents has been analyzed. In conclusion the hybridization approach gave a new serie of multitarget antiinflammatory compounds, characterized by a strong antioxidant activity in different biological targets.
Topics: Anti-Inflammatory Agents; Blood Platelets; Cell Survival; Chemotaxis; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Male; Neutrophils; Oxidation-Reduction; Phosphodiesterase 4 Inhibitors; Platelet Aggregation; Pyrazoles; Reactive Oxygen Species; Structure-Activity Relationship
PubMed: 32085423
DOI: 10.3390/molecules25040899 -
Molecules (Basel, Switzerland) Aug 2021Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities;... (Review)
Review
Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities; however, few have dealt with the chemistry and the biology of heteroannulated derivatives. Therefore, we focused our attention on recent topics, up until 2020, for the synthesis of pyrazoles, their heteroannulated derivatives, and their applications as biologically active moieties. Moreover, we focused on traditional procedures used in the synthesis of pyrazoles.
Topics: Chemistry Techniques, Synthetic; Humans; Pyrazoles
PubMed: 34443583
DOI: 10.3390/molecules26164995 -
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 -
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 -
International Journal of Molecular... May 20204-Pyrazoles are emerging scaffolds for "click" chemistry. Late-stage fluorination with Selectfluor is found to provide a reliable route to 4-fluoro-4-methyl-4-pyrazoles....
4-Pyrazoles are emerging scaffolds for "click" chemistry. Late-stage fluorination with Selectfluor is found to provide a reliable route to 4-fluoro-4-methyl-4-pyrazoles. 4-Fluoro-4-methyl-3,5-diphenyl-4-pyrazole (MFP) manifested 7-fold lower Diels-Alder reactivity than did 4,4-difluoro-3,5-diphenyl-4-pyrazole (DFP), but higher stability in the presence of biological nucleophiles. Calculations indicate that a large decrease in the hyperconjugative antiaromaticity in MFP relative to DFP does not lead to a large loss in Diels-Alder reactivity because the ground-state structure of MFP avoids hyperconjugative antiaromaticity by distorting into an envelope-like conformation like that in the Diels-Alder transition state. This predistortion enhances the reactivity of MFP and offsets the decrease in reactivity from the diminished hyperconjugative antiaromaticity.
Topics: Chemistry Techniques, Synthetic; Cycloaddition Reaction; Fluorine; Glutathione; Kinetics; Models, Molecular; Molecular Conformation; Molecular Structure; Organic Chemicals; Pyrazoles; Stereoisomerism; Thermodynamics; Ultraviolet Rays
PubMed: 32486503
DOI: 10.3390/ijms21113964 -
Expert Opinion on Therapeutic Patents Mar 2012Pyrazolines are well-known and important nitrogen-containing five-membered ring heterocyclic compounds. Various methods have been worked out for their synthesis. Several... (Review)
Review
INTRODUCTION
Pyrazolines are well-known and important nitrogen-containing five-membered ring heterocyclic compounds. Various methods have been worked out for their synthesis. Several pyrazoline derivatives have been found to possess diverse biological properties, which has stimulated research activity in this field.
AREAS COVERED
The present review sheds light on the recent therapeutic patent literature (2000 - 2011) describing the applications of pyrazolines and their derivatives on selected activities. Many of the therapeutic applications of pyrazoline derivatives have been discussed, either in the patent or in the general literature areas in this review. In addition to selected biological data, a wide range of pharmaceutical applications and pharmaceutical compositions are also summarized.
EXPERT OPINION
Pyrazoline derivatives have numerous prominent pharmacological effects, such as antimicrobial (antibacterial, antifungal, antiamoebic, antimycobacterial), anti-inflammatory, analgesic, antidepressant and anticancer. Further pharmacological effects include cannabinoid CB1 receptor antagonists, antiepileptic, antitrypanosomal, antiviral activity, MAO-inhibitory, antinociceptive activity, insecticidal, hypotensive, nitric oxide synthase inhibitor, antioxidant, steroidal and antidiabetic. Lastly, they also effect ACAT inhibition, urotensin II and somatostatin-5 receptors, TGF-β signal transduction inhibitors and neurocytotoxicity inhibitors activities. Many new pyrazoline derivatives have been synthesized and patented, but there are still new aspects to explore and work on.
Topics: Animals; Drug Delivery Systems; Drug Design; Humans; Patents as Topic; Pyrazoles
PubMed: 22397588
DOI: 10.1517/13543776.2012.667403 -
Journal of Enzyme Inhibition and... Dec 2023Design and synthesis of three novel series of aryl enaminones (- and -) and pyrazole () linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid...
Effect of hydrophobic extension of aryl enaminones and pyrazole-linked compounds combined with sulphonamide, sulfaguanidine, or carboxylic acid functionalities on carbonic anhydrase inhibitory potency and selectivity.
Design and synthesis of three novel series of aryl enaminones (- and -) and pyrazole () linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO hydrase assay. Enaminone sulphonamide derivatives (-) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds and were further screened for their cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC = 4.918 and 12.27 µM, respectively) and hypoxic (IC = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.
Topics: Humans; Carbonic Anhydrases; Carbonic Anhydrase IX; Sulfaguanidine; Structure-Activity Relationship; Carboxylic Acids; Sulfonamides; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Pyrazoles; Molecular Structure
PubMed: 37078174
DOI: 10.1080/14756366.2023.2201403