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International Journal of Molecular... Oct 2023A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for...
A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products. In the case of the protected fleximer base, 1-(4-benzyloxypyrimidin-5-yl)pyrazole, the reaction proceeded selectively with formation of only one product. However, both synthetic routes to realize the fleximer ribonucleoside () worked with equal efficiency. The new compounds, as well as some 8-aza-7-deazapurine nucleosides synthesized previously, were studied against Gram-positive and Gram-negative bacteria and . It was shown that 1-(β-D-ribofuranosyl)-4-(2-aminopyridin-3-yl)pyrazole () and 1-(2',3',4'-trihydroxycyclopent-1'-yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole () were able to inhibit the growth of mc2 155 by 99% at concentrations (MIC) of 50 and 13 µg/mL, respectively. Antimycobacterial activities were revealed for 4-(4-aminopyridin-3-yl)-1H-pyrazol () and 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-4-(4-benzyloxypyrimidin-5-yl)pyrazole (). At concentrations (MIC) of 40 and 20 µg/mL, respectively, the compounds resulted in 99% inhibition of growth.
Topics: Humans; Anti-Bacterial Agents; Nucleosides; Gram-Negative Bacteria; Gram-Positive Bacteria; Mycobacterium tuberculosis; Tuberculosis; Pyrazoles; Microbial Sensitivity Tests; Structure-Activity Relationship
PubMed: 37895100
DOI: 10.3390/ijms242015421 -
Cells Jan 2022In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue...
In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.
Topics: Caspases; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Screening Assays, Antitumor; Enzyme Activation; Exocytosis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Microtubules; Neoplasm Invasiveness; Neoplasm Proteins; Phosphatidylserines; Phosphorylation; Poly(ADP-ribose) Polymerases; Pyrazoles; Reactive Oxygen Species; Signal Transduction; Spindle Apparatus; Triple Negative Breast Neoplasms; Tubulin
PubMed: 35053370
DOI: 10.3390/cells11020254 -
Scientific Reports Apr 2023Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and...
Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of CA IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with ICs' of 45.88, 28.27, and 16.57 uM, 25.01, 8.99, and 3.27 µM, respectively. Both compounds induced cellular apoptosis on HCT-116 and SW-620 cells, while compound 3 induced necrosis as well. In addition, both compounds induced cell cycle arrest on G0/G1, and S phases. Also, compound 11 showed potential autophagy induction on both colon cancer cell lines (HCT-116, and HT-29), and a little bit on metastatic type. Both compounds were less cytotoxic than the reference drug on normal epithelial cell. The migration rates of HCT-116 and the metastatic one SW-620 were reduced by both compounds. Finally, molecular docking of compounds 3 and 11 into the active site of CA IX confirmed in vitro inhibitory activity for both compounds.
Topics: Humans; Structure-Activity Relationship; Molecular Docking Simulation; Carbonic Anhydrase IX; Sulfonamides; Antineoplastic Agents; Colonic Neoplasms; Apoptosis; Pyrazoles; Molecular Structure; Cell Proliferation
PubMed: 37031294
DOI: 10.1038/s41598-023-32820-0 -
Molecules (Basel, Switzerland) Nov 2019Due to a significant and prolific activity in the field of design and synthesis of new energetic molecules, it becomes increasingly difficult to introduce new...
Due to a significant and prolific activity in the field of design and synthesis of new energetic molecules, it becomes increasingly difficult to introduce new explosophore structures with attractive properties. In this work, we synthesized a trans-bimane-based energetic material-3,7-diamino-2,6-dinitro-1,5-pyrazolo-[1,2-a]pyrazole-1,5-dione (4), the structure of which was comprehensively analyzed by a variety of advanced spectroscopic methods and by X-ray crystallo-graphy (with density of 1.845 g·cm at 173 K). Although obtained crystals of 4 contained solvent molecules in their structure, state-of-the-art density functional theory (DFT) computational techniques allowed us to predict that solvent-free crystals of this explosive would preserve a similar tightly packed planar layered molecular arrangement, with the same number of molecules of 4 per unit cell, but with a smaller unit cell volume and therefore higher energy density. Explosive 4 was found to be heat resistant, with an onset decomposition temperature of 328.8 °C, and was calculated to exhibit velocity of detonation in a range of 6.88-7.14 km·s and detonation pressure in the range of 19.14-22.04 GPa, using for comparison both HASEM and the EXPLO 5 software. Our results indicate that the -bimane explosophore could be a viable platform for the development of new thermostable energetic materials.
Topics: Bridged Bicyclo Compounds, Heterocyclic; Explosive Agents; Hot Temperature; Pyrazoles; Software; Solvents; Thermodynamics
PubMed: 31779257
DOI: 10.3390/molecules24234324 -
Epilepsia Apr 2022As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability....
OBJECTIVE
As a key member of the transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine-induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 only provides limited benefits in pilocarpine-treated mice, likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW-65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW-65 on seizure susceptibility.
METHODS
We first examined the pharmacokinetic properties including plasma half-life and brain to plasma ratio of JW-65 after systemic administration in mice. We then investigated the effects of TRPC3 inhibition by JW-65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW-65-treated mice to pentylenetetrazole (PTZ)-induced seizures with phenytoin as a comparator.
RESULTS
JW-65 showed adequate half-life and brain penetration in mice, justifying its use for central nervous system conditions. Systemic treatment with JW-65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW-65 was administered after pilocarpine-induced behavioral seizures were well established and was confirmed by time-locked electroencephalographic monitoring and synchronized video. Moreover, JW-65-treated mice showed substantially decreased susceptibility to PTZ-induced seizures in a dose-dependent manner.
SIGNIFICANCE
These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW-65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this proof-of-concept study establishes TRPC3 as a novel feasible therapeutic target for the treatment of some forms of epilepsy.
Topics: Animals; Disease Models, Animal; Mice; Pentylenetetrazole; Pilocarpine; Pyrazoles; Seizures
PubMed: 35179226
DOI: 10.1111/epi.17190 -
Molecules (Basel, Switzerland) Sep 2010Pyrano[2,3-c]pyrazoles are obtained via mixing ethyl acetoacetate, hydrazine hydrate, aldehydes or ketones and malononitrile in the absence of solvent. These same...
Pyrano[2,3-c]pyrazoles are obtained via mixing ethyl acetoacetate, hydrazine hydrate, aldehydes or ketones and malononitrile in the absence of solvent. These same products were also obtained by reacting arylidenemalononitriles 3 with 3-methyl-2-pyrazolin-5-ones. NOE difference experiments confirmed that these products exist solely in the 2H form. Similar treatments of 3-amino-2-pyrazolin-5-one with arylidene-malononitrile afforded adduct 6. Similarly mixing ethyl cyanoacetate, hydrazine hydrate, aldehydes, with malononitrile gave the same product 6. A novel synthesis of 4-oxo-4H-pyrano[2,3-c]pyrazole (8) could be achieved via reacting 3-methyl-2-pyrazolin-5-one with a mixture of cyanoacetic acid and acetic anhydride. Similar treatment of 3-aminopyrazole 11 with the benzylidene-malononitrile produced the pyrazolo[2,3-a]pyrimidines 12a,b.
Topics: Green Chemistry Technology; Pyrazoles; Pyrimidines
PubMed: 20877248
DOI: 10.3390/molecules15096619 -
Journal of Medicinal Chemistry Nov 2020We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor...
We report herein the design, synthesis, and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides as selective androgen receptor degraders (SARDs) and pan-antagonists that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated that introducing a pyrazole moiety as the B-ring structural element in the common A-ring-linkage-B-ring nonsteroidal antiandrogens' general pharmacophore allowed the development of a new scaffold of small molecules with unique SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-155 () and UT-34 (). Novel B-ring pyrazoles exhibited potent AR antagonist activities, including promising distribution, metabolism, and pharmacokinetic properties, and broad-spectrum AR antagonist properties, including potent antitumor activity. was able to induce an 80% tumor growth inhibition of xenografts derived from the enzalutamide-resistant (Enz-R) VCaP cell line. These results represent an advancement toward the development of novel AR antagonists for the treatment of Enz-R prostate cancer.
Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Half-Life; Humans; Male; Mice; Microsomes, Liver; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Structure-Activity Relationship; Xenograft Model Antitumor Assays
PubMed: 33095584
DOI: 10.1021/acs.jmedchem.0c00943 -
Nature Communications Sep 2022Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological...
Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well.
Topics: Benzodioxoles; Protein Aggregates; Pyrazoles; alpha-Synuclein
PubMed: 36104315
DOI: 10.1038/s41467-022-32797-w -
Journal of Labelled Compounds &... Aug 2017JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB R) receptor. Peripheral CB receptor antagonists/inverse agonists have...
Synthesis of S-2-((S)-3-(4-chlorophenyl)-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamido)-3-(methyl-d )butanamide-d , octadeuterated JD5037.
JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB R) receptor. Peripheral CB receptor antagonists/inverse agonists have great potential in the treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated [ H ]-JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L-valine-d starting material. The [ H ]-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard.
Topics: Amides; Chemistry Techniques, Synthetic; Deuterium; Models, Molecular; Molecular Conformation; Pyrazoles; Receptor, Cannabinoid, CB1; Sulfonamides
PubMed: 28545167
DOI: 10.1002/jlcr.3521 -
Molecules (Basel, Switzerland) Aug 2023On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF were designed and synthesized. Their...
On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF were designed and synthesized. Their chemical structures were characterized by H and C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 μg/mL. Compounds and exhibited higher activity against all the tested fungi, and displayed the highest activity against with an EC value of 0.0530 μM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.
Topics: Antifungal Agents; Pyrazoles; Mass Spectrometry; Mycelium
PubMed: 37687108
DOI: 10.3390/molecules28176279