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The Journal of Organic Chemistry Aug 2022Inspired by crystal structures, we designed and achieved a catalyst-free Michael reaction for the preparation of an N1-alkyl pyrazole in a high yield (>90%) with...
Inspired by crystal structures, we designed and achieved a catalyst-free Michael reaction for the preparation of an N1-alkyl pyrazole in a high yield (>90%) with excellent regioselectivity (N1/N2 > 99.9:1). The scope of this protocol has been extended to accomplish the first general regioselective N1-alkylation of 1-pyrazoles to give di-, tri-, and tetra-substituted pyrazoles in a single step. The resulting pyrazoles bear versatile functional groups such as bromo, ester, nitro, and nitrile, offering opportunities for late-stage functionalization. This efficient methodology will have an impact on drug discovery, as several Food and Drug Administration-approved drugs are pyrazole derivatives. A working hypothesis for the regioselectivity is proposed. X-ray crystal structures of the products that highlight the attractive interactions are discussed. This report provides a rare source for the further elucidation of the attractive interactions because the isomeric ratios and the crystal structures are directly related.
Topics: Alkylation; Catalysis; Isomerism; Pyrazoles
PubMed: 35877958
DOI: 10.1021/acs.joc.2c00980 -
Medicinal Chemistry (Shariqah (United... 2022Quinoline is a well-established nucleus displaying various biological activities. Quinolin-8-ol-containing compounds are reported for antimicrobial as well as...
BACKGROUND
Quinoline is a well-established nucleus displaying various biological activities. Quinolin-8-ol-containing compounds are reported for antimicrobial as well as antimalarial activity. Hydrazone- and pyrazole-containing compounds are also reported for antimicrobial activity. In this work, we have synthesized hydrazonomethyl-quinolin-8-ol and pyrazol-3-yl-quinolin-8-ol derivatives retaining quinolin-8-ol along with hydrazone/pyrazole pharmacophores.
OBJECTIVE
The objective of this work was to synthesise and evaluate in vitro hydrazonomethylquinolin- 8-ol and pyrazol-3-yl-quinolin-8-ol derivatives for antifungal, antibacterial and antimalarial activity.
METHODS
Designed and synthesized hydrazonomethyl-quinolin-8-ol and pyrazol-3-yl-quinolin-8- ol derivatives were evaluated for antifungal (against Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans), antibacterial (against methicillin resistant Staphylococcus aureus (MRSA), Escherichia Coli, Pseudomonas aeruginosa and Klebsillae pneumoniae) as well as antimalarial (against Plasmodium falciparum D6 and W2 strains) activity.
RESULTS
Hydrazonomethyl-quinolin-8-ol (15.1-15.28) and pyrazol-3-yl-quinolin-8-ol derivatives (16.1-16.21 and 20.1-20.18) were synthesized in good to moderate yield. One-pot synthesis of pyrazol- 3-yl-quinolin-8-ol derivatives (16.1-16.21 and 20.1-20.18) was achieved. Compounds 15.3, 15.6, 15.7, 15.9-15.14, 15.16-15.19, 15.22 and 15.24 were found more potent compared to reference standard fluconazole (IC = 3.20 μM) against C. albicans with IC value less than 3 μM. Compounds 15.1, 15.2, 15.21 and 15.23 showed almost similar activity to reference standard fluconazole against C. albicans. Compounds 15.1-15.3, 15.9-15.12, 15.14-15.17, and 15.21-15.23 also showed good activity against fluconazole-resistant strain A. fumigatus with IC50 value less than 3 μM. Compounds 15.2-15.4, 15.7, 15.9, 15.17, 15.20 showed good antimalarial activity against P. falciparum D6 as well as P. falciparum W2 with IC50 values of 1.84, 1.83, 1.56, 1.49, 1.45, 1.97, 1.68 μM and 1.86, 1.40, 1.19, 1.71, 1.16, 1.34, 1.61 μM, respectively. 5-Pyrazol-3-yl-quinolin-8-ol derivatives, such as 16.3, 16.5, 16.11, 16.13, 16.19, 16.20, also showed antimalarial activity against P. falciparum D6 and W2 strains with IC50 values of 2.23, 2.16, 2.99, 2.99, 2.73, 2.12 μM and 2.91, 3.60, 4.61, 2.71, 2.31, 2.66 μM, respectively.
CONCLUSION
Most of the 5-hydrazonomethyl-quinolin-8-ol derivatives showed good antifungal activity against C. albicans, A. fumigatus and C. neoformans. Most of the 5-hydrazonomethylquinolin- 8-ol derivatives were found more potent than reference standard fluconazole. These derivatives may be considered as leads for further development of antifungal agents.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antimalarials; Candida albicans; Cryptococcus neoformans; Escherichia coli; Fluconazole; Hydrazones; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pyrazoles; Structure-Activity Relationship
PubMed: 35240963
DOI: 10.2174/1573406418666220303144929 -
Molecules (Basel, Switzerland) Dec 2019Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex... (Review)
Review
Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.
Topics: Chemistry, Pharmaceutical; Molecular Structure; Pyrazoles; Pyrimidines; Structure-Activity Relationship
PubMed: 31877672
DOI: 10.3390/molecules25010042 -
Molecular Diversity Aug 20195-Amino-pyrazoles have proven to be a class of fascinating and privileged organic tools for the construction of diverse heterocyclic or fused heterocyclic scaffolds.... (Review)
Review
5-Amino-pyrazoles have proven to be a class of fascinating and privileged organic tools for the construction of diverse heterocyclic or fused heterocyclic scaffolds. This review presents comprehensively the applications of 5-amino-pyrazoles as versatile synthetic building blocks in the synthesis of remarkable organic molecules with an emphasis on versatile functionalities. Following a brief introduction of synthesis methods, planning strategies to construct organic compounds, particularly diverse heterocyclic scaffolds, such as poly-substituted heterocyclic compounds and fused heterocyclic compounds via 5-amino-pyrazoles, have been summarized. Fused heterocycles are classified as bicyclic, tricyclic, tetracyclic, and spiro-fused pyrazole derivatives. These outstanding compounds synthesized via wide variety of approaches include conventional reactions, one-pot multi-component reactions, cyclocondensation, cascade/tandem protocols, and coupling reactions. 5-Amino-pyrazoles represent a class of promising functional reagents, similar to the biologically active compounds, highlighted with diverse applications especially in the field of pharmaceutics and medicinal chemistry. Notably, this critical review covers the articles published from 1981 to 2018.
Topics: Chemistry Techniques, Synthetic; Chemistry, Pharmaceutical; Indicators and Reagents; Pyrazoles
PubMed: 30552550
DOI: 10.1007/s11030-018-9902-8 -
Mini Reviews in Medicinal Chemistry 2021Pyrazole and its derivatives are a pharmacologically and significantly active scaffolds that have innumerable physiological and pharmacological activities. They can be... (Review)
Review
Pyrazole and its derivatives are a pharmacologically and significantly active scaffolds that have innumerable physiological and pharmacological activities. They can be very good targets for the discovery of novel anti-bacterial, anti-cancer, anti-inflammatory, anti-fungal, anti-tubercular, antiviral, antioxidant, antidepressant, anti-convulsant and neuroprotective drugs. This review focuses on the importance of in silico manipulations of pyrazole and its derivatives for medicinal chemistry. The authors have discussed currently available information on the use of computational techniques like molecular docking, structure-based virtual screening (SBVS), molecular dynamics (MD) simulations, quantitative structure activity relationship (QSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to drug design using pyrazole moieties. Pyrazole based drug design is mainly dependent on the integration of experimental and computational approaches. The authors feel that more studies need to be done to fully explore the pharmacological potential of the pyrazole moiety and in silico method can be of great help.
Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Binding Sites; Drug Design; Drug Resistance, Microbial; Edema; Molecular Docking Simulation; Pyrazoles; Quantitative Structure-Activity Relationship
PubMed: 32875985
DOI: 10.2174/1389557520666200901184146 -
Future Medicinal Chemistry Aug 2023Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent... (Review)
Review
Chemotherapy is a critical treatment modality for cancer patients, but multidrug resistance remains one of the major challenges in cancer therapy, creating an urgent need for the development of novel potent chemical entities. Azoles, particularly pyrazole, could interact with different biological targets and exhibit diverse biological properties including anticancer activity. Many clinically used anticancer agents own an azole moiety, demonstrating that azoles are privileged and pivotal templates in the discovery of novel anticancer chemotherapeutics. The present article is an attempt to highlight the recent advances in pyrazole-azole hybrids with anticancer potential and discuss the structure-activity relationships, covering articles published from 2018 to present, to facilitate the rational design of more effective anticancer candidates.
Topics: Humans; Azoles; Structure-Activity Relationship; Antineoplastic Agents; Neoplasms; Pyrazoles
PubMed: 37610862
DOI: 10.4155/fmc-2023-0138 -
Chemical Biology & Drug Design Sep 2022Among the various heterocyclic molecules employed for drug design and discovery, pyrazolopyridine is one of the promising pharmacophores. Pyrazolopyridine is a result of... (Review)
Review
Among the various heterocyclic molecules employed for drug design and discovery, pyrazolopyridine is one of the promising pharmacophores. Pyrazolopyridine is a result of fusion of pyrazole and pyridine rings. The potent pharmacology of pyrazolopyridine may be the synergistic effect of pyrazole and pyridine moieties in a single framework. It has been used in drug design of a wide range of diseases such as anticancer, antimicrobial, anti-inflammatory, and neuroprotection. Cancer has become a common disease among elderly people now a days that might be because of genetic inheritance to some extent, carcinogens, pollution, and some infectious diseases. Whatever may be the reason, cancer is one of the major causes of deaths worldwide. In addition, over-usage and improper usage of antibiotics have led to drug resistance of microbes. Further, inflammation is a cause of various diseases such as arthritis, and other diseases. Thus, proinflammatory kinases are considered as primary target for inhibition of inflammation. In view of this, a work that compiles potent pharmacology of recently reported pyrazolopyridine analogs has been planned. The review is aimed to discuss pharmacology in brief along with structure-activity relationship (SAR). The review would emphasize importance of pyrazolopyridines in future drug design and discovery and may help in design of potent pharmacological agents.
Topics: Aged; Drug Design; Humans; Inflammation; Molecular Structure; Pyrazoles; Pyridines; Structure-Activity Relationship
PubMed: 35661410
DOI: 10.1111/cbdd.14098 -
Scientific Reports Mar 2020Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate...
Bipyrazone, 1,3-dimethyl-4-(2-(methylsulfonyl)-4-(trifluoromethyl) benzoyl)-1H-pyrazol-5-yl 1,3-dimethyl-1H-pyrazole- 4-carboxylate, is a 4-hydroxyphenylpyaunate dioxygenase (HPPD)-inhibiting herbicide. Greenhouse and field experiments were conducted to explore the potential of post-emergence (POST) application of bipyrazone in wheat fields in China. In the greenhouse study, bipyrazone at 10 and 20 g active ingredient (a.i.) ha effectively controlled Descurainia sophia L., Capsella bursa-pastoris (L.) Medic., Lithospermum arvense L. and Myosoton aquaticum L. Whereas, all tested 16 wheat cultivars showed high degree of tolerance to bipyrazone at 375 and 750 g a.i. ha. In a dose-response experiment carried on the Shannong 6 wheat cultivar and five weed biotypes, bipyrazone was safe to the wheat cultivar, and C. bursa-pastoris, M. aquaticum and D. sophia were sensitive to this herbicide. The selectivity index (SI) between the Shannong 6 and weeds ranged from 34 to 39. The field experiments confirmed that a mixture of bipyrazone and fluroxypyr-mepthyl is practical for controlling broadleaf weeds, and bipyrazone applied alone at 30 to 40 g a.i. ha can also provide satisfactory control of sensitive broadleaf weeds. These findings suggest that bipyrazone POST application has good potential for broadleaf weed management in wheat fields.
Topics: 4-Hydroxyphenylpyruvate Dioxygenase; Crops, Agricultural; Greenhouse Effect; Herbicide Resistance; Herbicides; Molecular Structure; Plant Proteins; Plant Weeds; Pyrazoles; Triticum
PubMed: 32218463
DOI: 10.1038/s41598-020-62116-6 -
Organic & Biomolecular Chemistry Nov 2022Condensation of 1,5-disubstituted pent-1-en-4-yn-1-ones with arylhydrazines in acidified alcohol results mainly in the formation of the corresponding arylhydrazones with...
Condensation of 1,5-disubstituted pent-1-en-4-yn-1-ones with arylhydrazines in acidified alcohol results mainly in the formation of the corresponding arylhydrazones with traces of the side products of cyclization at the double bond - 1,5-diaryl-3-(arylethynyl)-4,5-dihydro-1-pyrazoles (pyrazolines). Arylhydrazones are cyclized only by refluxing in high-boiling polar solvents (DMF and ethylene glycol), with the selective formation of 1,5-disubstituted 3-styrylpyrazoles in up to 77-95% yields. Thermodynamically, the cyclization of arylhydrazones at the triple bond is the most preferable pathway, as shown by DFT calculations and preparative synthesis experiments. Thus, we demonstrate that the reactions of arylhydrazines with 1,5-disubstituted pent-1-en-4-yn-1-ones lead to the formation of arylhydrazones and side pyrazoline impurities in a parallel (not consecutive) manner. 2-Hydrazinylpyridine interacts with 1,5-disubstituted pent-1-en-4-yn-1-ones in some other way, giving not pyridinylhydrazones but 2-(5-styryl-3-phenyl-1-pyrazol-1-yl)pyridines (despite the acidity of the medium). The authors have developed a gram-scale synthesis method for these compounds, which were obtained in up to 60-82% yields. Besides, we have developed the synthesis method for certain styrylpyrazoles, which are quite promising substances for use as fluorescent probes. Their spectral-luminescence characteristics were examined as well as their complexing with Hg, Cd, and Pb ions.
Topics: Cyclization; Luminescence; Pyrazoles; Pyridines
PubMed: 36285801
DOI: 10.1039/d2ob01427k -
Cellular & Molecular Biology Letters Dec 2021Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and...
BACKGROUND
Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and pathological processes. However, the detailed signaling pathway of ESD remains poorly understood.
METHODS
Considering the advantages of the small chemical molecule, our recent work demonstrated that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) activates ESD, and will be a good tool for studying ESD further. Firstly, we determined the interaction between ESD and FK506 binding protein 25 (FKBP25) by yeast two-hybrid assay and co-immunoprecipitation (CO-IP) and analyzed the phosphorylation levels of mTORC1, P70S6K and 4EBP1 by western blot. Furthermore, we used the sulforhodamine B (SRB) and chick chorioallantoic membrane (CAM) assay to analyze cell viability in vitro and in vivo after treatment with ESD activator FPD5.
RESULTS
We screened FKBP25 as a candidate protein to interact with ESD by yeast two-hybrid assay. Then we verified the interaction between ESD and endogenous FKBP25 or ectopically expressed GFP-FKBP25 by CO-IP. Moreover, the N-terminus (1-90 aa) domain of FKBP25 served as the crucial element for their interaction. More importantly, ESD reduced the K48-linked poly-ubiquitin chains of FKBP25 and thus stabilized cytoplasmic FKBP25. ESD also promoted FKBP25 to bind more mTORC1, suppressing the activity of mTORC1. In addition, ESD suppressed tumor cell growth in vitro and in vivo through autophagy.
CONCLUSIONS
These findings provide novel evidence for elucidating the molecular mechanism of ESD and ubiquitination of FKBP25 to regulate autophagy and cancer cell growth. The ESD/FKBP25/mTORC1 signaling pathway is involved in inhibiting tumor cell growth via regulating autophagy.
Topics: Animals; Autophagy; Cell Cycle; Cell Line; Cell Line, Tumor; Chickens; HEK293 Cells; HeLa Cells; Humans; Mechanistic Target of Rapamycin Complex 1; Phosphorylation; Pyrazoles; Signal Transduction; Tacrolimus; Tacrolimus Binding Proteins; Thiolester Hydrolases; Ubiquitination
PubMed: 34875997
DOI: 10.1186/s11658-021-00297-2