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Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application.Chemistry & Biodiversity Feb 2019Curcumin is an admired, plant-derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is... (Review)
Review
Curcumin is an admired, plant-derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin are reported to seize this limitation; such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal points of these reviews are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community.
Topics: Animals; Chemistry, Pharmaceutical; Curcumin; Drug Stability; Humans; Isoxazoles; Pyrazoles
PubMed: 30460748
DOI: 10.1002/cbdv.201800366 -
Current Topics in Medicinal Chemistry 2019Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds....
BACKGROUND
Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds. Efforts were made to optimize the structure with bioisosteric replacement of 1,3-diketo functional group with the corresponding pyrazole and isoxazole moieties.
OBJECTIVE
The goal of this paper is designing new hispolon isoxazole and pyrazole and the evaluation of their biological activities.
METHODS
The designed compounds were prepared using classical organic synthesis methods. The anti- TB activity was evaluated using the MABA method.
RESULTS
A total of 44 compounds were synthesized (1a- 1v and 2a-2v) and screened for anti TB activity and antibacterial activity. The compounds 1b and 1n showed the highest potency with MIC 1.6µg/mL against M. tuberculosis H37Rv.
CONCLUSION
Bioisosteric replacement of 1,3-diketo functional group in hispolons with pyrazole or isoxazole rings have resulted in potent anti TB molecules. Docking simulations of these compounds on mtFabH enzyme resulted in a clear understanding of bioactivity profiles of these compounds. Docking scores are in good agreement with the anti TB activity obtained for these compounds. Computational studies and in vitro screening results indicate mtFabH as the probable target of these compounds.
Topics: Antitubercular Agents; Catechols; Drug Evaluation, Preclinical; Isoxazoles; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles
PubMed: 30834836
DOI: 10.2174/1568026619666190305124954 -
The Journal of Organic Chemistry Dec 2022Here, we report the synthesis of 3,4-disubstituted 1-pyrazoles and 3,5-disubstituted pyridines from the reaction of epoxides with hydrazine and ammonia, respectively....
Here, we report the synthesis of 3,4-disubstituted 1-pyrazoles and 3,5-disubstituted pyridines from the reaction of epoxides with hydrazine and ammonia, respectively. Both reactions utilize Sc(OTf) as a Lewis acid. The pyrazole synthesis utilizes -bromosuccinimide to convert the intermediate pyrazolines to the pyrazoles, whereas the pyridine synthesis utilizes FeCl as a cocatalyst.
Topics: Pyridines; Ammonia; Epoxy Compounds; Pyrazoles; Hydrazines
PubMed: 36475626
DOI: 10.1021/acs.joc.2c02544 -
ChemMedChem Oct 2020In search of novel and effective antitumor agents, pyrazoline-substituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro...
In search of novel and effective antitumor agents, pyrazoline-substituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC =0.78±0.01 μM), HT29 (IC =0.92±0.15 μM) and K562 (IC =47.25±1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1-(2-(3-(4-fluorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione). In cell-cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G /G phase and decreased cell population in G /M phase. The excellent in vitro effects were also supported by inhibition of anti-apoptotic protein Bcl-2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine-2,5-dioes holds promise for the development of more potent and less toxic anticancer agents.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Molecular Structure; Neoplasms, Experimental; Pyrazoles; Pyrrolidines; Structure-Activity Relationship
PubMed: 32715626
DOI: 10.1002/cmdc.202000458 -
Bioorganic & Medicinal Chemistry Letters Jun 2021Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design...
Myeloperoxidase (MPO), a critical enzyme in antimicrobial host-defense, has been implicated in chronic inflammatory diseases such as coronary artery disease. The design and evaluation of MPO inhibitors for the treatment of cardiovascular disease are reported herein. Starting with the MPO and triazolopyridine 3 crystal structure, novel inhibitors were designed incorporating a substituted pyrazole, which allowed for substituents to interact with hydrophobic and hydrophilic patches in the active site. SAR exploration of the substituted pyrazoles led to piperidine 17, which inhibited HOCl production from activated neutrophils with an IC value of 2.4 μM and had selectivity against thyroid peroxidase (TPO). Optimization of alkylation chemistry on the pyrazole nitrogen facilitated the preparation of many analogs, including macrocycles designed to bridge two hydrophobic regions of the active site. Multiple macrocyclization strategies were pursued to prepare analogs that optimally bound to the active site, leading to potent macrocyclic MPO inhibitors with TPO selectivity, such as compound 30.
Topics: Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Macrocyclic Compounds; Molecular Structure; Peroxidase; Pyrazoles; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 33811992
DOI: 10.1016/j.bmcl.2021.128010 -
Chemistry & Biodiversity Sep 2021In this study, the synthesis of new spiropyrazoles, pyrazole and hydantoin heterocycles is reported by three component reactions of parabanic acids, hydrazine...
In this study, the synthesis of new spiropyrazoles, pyrazole and hydantoin heterocycles is reported by three component reactions of parabanic acids, hydrazine derivatives, and phenacyl bromides in the presence of triphenylphosphine as a nucleophile and triethylamine as a base in good to high yields (69-91 %). Evaluation of the synthesized compounds revealed a good to excellent antioxidant activities (37.6-96.2 %) using DPPH inhibitory potency. Among these compounds, hydantoin derivatives displayed higher antioxidant activities (93.7-96.2 %) comparing with spiropyrazoles and pyrazoles. The obtained results showed that Cl and Br substituents on the phenyl ring increased antioxidant activities of the related heterocycles. The antibacterial activities of the synthesized compounds were examined against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. Among the synthesized heterocycles, 2-[1,3-dimethyl-2,5-dioxo-4-(2-oxo-2-phenylethyl)imidazolidin-4-yl]hydrazine-1-carbothioamide exhibited the excellent antibacterial activity against both Gram-positive and Gram-negative bacteria.
Topics: Anti-Bacterial Agents; Antioxidants; Biphenyl Compounds; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Structure; Picrates; Pyrazoles; Spiro Compounds
PubMed: 34272925
DOI: 10.1002/cbdv.202100197 -
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 -
Current Drug Discovery Technologies 2023In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of...
BACKGROUND
In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of 4-(((7-amino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl- 2-phenyl-1H-pyrazol-3(2H)-one were synthesized and assessed for their antibacterial and anticancer activity.
OBJECTIVE
Encouraged by these results, these analogues 4-(((7-amino-7H-[1,2,4]triazolo[4,3- b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones 8 have been synthesized and their inhibitory potential activity against different bacterial microorganisms and cancer cell lines was discussed.
METHODS
All the synthesized final scaffolds were characterized by H NMR, C NMR, IR, mass and elemental analysis. All the synthesized 1,2,4-triazole linked to pyrazole compounds were evaluated for their antimicrobial sensitivity by using the agar dilution technique. The anticancer activity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and docking results are described by Autodock 4.2.
RESULTS
In vitro analysis suggests that compounds 8h, 8f, and 8b demonstrated excellent antibacterial activity against S. aureus, P. aeruginosa, S. epidermidis with MICs of 8, 8, 11 μg/mL respectively, while the remaining compounds showed moderate to good inhibitory potential. Some of them exhibited potent cytotoxicity against MCF-7 and P388 cancer cell lines and compounds 8c, 8f, and 8d reveal the highest potency against MCF-7 with IC values 2.8 ± 0.4, 3.1 ± 0.4, 3.5 ± 0.2 μM, respectively. Especially 8c, 8i and 8f showed better interaction patterns with amino acids Ala197 (N-N), Lys168 (N-N), Asn163 (O-N) at 3.13, 3.09, 3.00 A° as reported in DNA (Topo II) complex (1ZXM).
CONCLUSION
New findings have established the fact that fused 1,2,4-triazoles linked to pyrazole contributed great significance in the field of medicinal chemistry due to their various biological properties.
Topics: Humans; Structure-Activity Relationship; Staphylococcus aureus; Triazoles; Anti-Bacterial Agents; Neoplasms; Pyrazoles; Molecular Structure; Antineoplastic Agents
PubMed: 36437730
DOI: 10.2174/1570163820666221125121625 -
Bioorganic & Medicinal Chemistry Letters Aug 2022The synthesis of eight novel pyrazole-tetrazole compounds are presented. Their structures are identified by NMR and FTIR spectroscopy, mass spectrometry as well as...
The synthesis of eight novel pyrazole-tetrazole compounds are presented. Their structures are identified by NMR and FTIR spectroscopy, mass spectrometry as well as elemental analysis. Their in-vitro α-amylase inhibition and haemoglobin antiglycation activity were examined by spectrophotometric methods. All compounds possess both activities, especially molecules entitled 2-(1-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-tetrazol-5-yl)pyridine 4 and 2-(1-((1-ethyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-tetrazol-5-yl)pyridine 8 which were found to be extremely potent compared to the positive controls. The SAR study proved the influence of the alkylation position of pyrazole derivative on the tetrazole ring, the nature of substituent on the tetrazolic carbon atom and the nature of the group at the nitrogen atom of the pyrazole ring on both α-amylase and glycation inhibition activity. Compounds 4 and 8 could be a good drug candidate to treat Type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Humans; Pyrazoles; Pyridines; Tetrazoles; alpha-Amylases
PubMed: 35569687
DOI: 10.1016/j.bmcl.2022.128785 -
Bioorganic & Medicinal Chemistry Jul 2022The apelin receptor (APJ) is a target for cardiovascular indications. Previously, we had identified a novel pyrazole-based agonist 1...
The apelin receptor (APJ) is a target for cardiovascular indications. Previously, we had identified a novel pyrazole-based agonist 1 ((S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide hydrochloride) of this GPCR. Systematic modification of 1 was performed to produce compounds with improved potency and ADME properties. Orally bioavailable compound 47 with favorable agonist potency (CaEC = 24 nM, cAMPi EC = 6.5 nM) and pharmacokinetic properties (clearance ∼20 mL/min/kg in rats) was identified. This compound has vastly reduced brain penetration and is devoid of significant off-target liability. In summary, a potent and selective APJ agonist suitable for in vivo studies of APJ in peripheral tissues after oral administration has been identified.
Topics: Animals; Apelin Receptors; Pyrazoles; Rats
PubMed: 35594649
DOI: 10.1016/j.bmc.2022.116789