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1.
J Fluoresc ; 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38381235

RESUMO

Zinc ions are one of the 2nd most abundant mineral after iron and it is important for immune system, enzymatic catalysis, DNA synthesis, and maintaining structural integrity in humans. But, monitoring the Zn levels in human body poses more challenges. This review paper investigates (paper from 2010 to 2023) the synthesis of pyrazoline derivatives by different methods, including conventional methods and green chemistry protocol. These Pyrazoline derivatives highlighted for their potential application as chemo-sensor for Zn2+ ions recognition. Pyrazoline compounds exhibit excellent sensitivity & selectivity and emitting blue-light with high quantum yields and electroluminescence, along with a superior limit of detection. These derivatives are stable bioactive molecule, with well-known diverse biological activities. This review not only gives valuable insights into the essential role of Zinc in human physiology but also provides a practical method for accurate Zinc detection in various samples. Which holds the potential for advancements in health diagnostics and environmental monitoring. Because of their significant biological application and selectivity as sensors, researchers have much more attention to prepare green environmentally-friendly pyrazoline derivatives.

2.
J Fluoresc ; 34(1): 159-167, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37166610

RESUMO

A fluorescent probe Y((1,1'-([1,1'-biphenyl]-4,4'-diylbis(3-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazole-5,1-diyl)) bis(ethan-1-one))) was designed and synthesized, which could be used to Cu2+ and Fe3+ sensors. Through the study of optical properties, the probe Y shows good selectivity and sensitivity to Cu2+ and Fe3+ in aqueous tetrahydrofuran solution [10.0 mM HEPES, pH 7.4, THF-H2O = 9:1(v/v)] with has excellent anti-interference performance, and its detection limits were 0.931 uΜ for Cu2+ and 0.401uΜ for Fe3+. The coordination mechanism of probe Y with Cu2+ and Fe3+ was speculated and verified at DFT level and HRNM. By Hela cytotoxicity and imaging tests, probe Y not only has good biocompatibility, but also can be used for sensing Cu2+ in cells.


Assuntos
Cobre , Corantes Fluorescentes , Humanos , Corantes Fluorescentes/química , Cobre/química , Ferro/química , Células HeLa , Imagem Óptica , Espectrometria de Fluorescência
3.
J Fluoresc ; 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38789859

RESUMO

The Pyrazoline derivatives display promising potential as sensitive and selective chemosensors for detecting Cu2+ ions. It has undergone screening for its sensing behavior with various metals using absorption, emission spectroscopic techniques. Their unique structure incorporates both donating and accepting sites, characterized by delocalized orbitals. These derivatives exhibit notable chromogenic and fluorogenic capabilities facilitated by intramolecular charge transfer. The sensors based on pyrazoline demonstrate exceptional selectivity, low detection limits, and precise detection of metal ions, particularly Cu2+. This review offers a comprehensive summary of recent discoveries concerning as pyrazoline-based "On-Off" chemosensors. The discussion places emphasis on exploring the design and photophysical properties of these chemosensors, with the primary objective of detecting Cu2+ metal ions. The unique features of pyrazoline derivatives make them promising candidates for practical applications in environmental and biological monitoring, showcasing their potential significance in advancing sensing technologies.

4.
Anal Bioanal Chem ; 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39191938

RESUMO

Biothiols, characterized by their unique sulfhydryl (-SH) groups, possess excellent antioxidant properties, effectively neutralizing the damage to cellular structures caused by reactive oxygen species (ROS) in living organisms. Additionally, lysosomes play a crucial role in decomposing damaged biomolecules through the action of their internal enzymes, regulating the cellular redox state, and mitigating oxidative stress. To facilitate rapid monitoring of intracellular biothiols, particularly within lysosomes, we constructed a lysosome-targeted biothiol fluorescent probe, PHL-DNP, in this study. PHL-DNP exhibited excellent photophysical properties in an aqueous test system, including strong fluorescence enhancement response, excellent selectivity, and low detection limits (Cys 16.5 nM, Hcy 16.8 nM, GSH 21.3 nM, Cap 26.6 nM). These attributes enabled easy and efficient qualification of Cys on test strips and accurate determination of the effective content of captopril tablets. Notably, PHL-DNP demonstrated low cytotoxicity and precise lysosomal targeting. Through bioimaging, PHL-DNP not only monitored changes in biothiol levels under oxidative stress but also assessed biothiols in complex biological systems such as live HeLa cells, zebrafish, tumor tissue sections, and radish roots. This provides a promising tool for quantitative analysis of biothiols, disease marker detection, and drug testing.

5.
Bioorg Chem ; 152: 107727, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39167872

RESUMO

Inflammation management presents a critical challenge in modern medicine, with nonsteroidal anti-inflammatory drugs (NSAIDs) being a widely used therapeutic option. However, their efficacy is often accompanied by significant gastrointestinal adverse effects, necessitating the exploration of safer alternatives, particularly through the investigation of cyclooxygenase-2 (COX-2) inhibitors. This study endeavors to address this imperative through the synthesis and evaluation of pyrazoline-phenoxyacetic acid derivatives. Among the synthesized compounds, 6a and 6c emerged as promising candidates, demonstrating potent COX-2 inhibition with IC50 values of 0.03 µM for both and selectivity index = 365.4 and 196.9, respectively. Furthermore, these compounds exhibited efficacy in mitigating formalin-induced edema in male Wistar rats, accompanied by favorable safety profiles upon histological examination of vital organs. Comprehensive safety assessments, including evaluation of creatinine, AST, and ALT enzymatic as well as troponin T and creatine kinase-MB levels, further reinforce the promising attributes of the synthetic candidates. Molecular docking studies endorsed by molecular dynamic simulations corroborate the biological findings, elucidating significant protein-ligand interactions at COX-2 active sites indicative of therapeutic potential.


Assuntos
Anti-Inflamatórios não Esteroides , Inibidores de Ciclo-Oxigenase 2 , Ciclo-Oxigenase 2 , Edema , Ratos Wistar , Animais , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Masculino , Ciclo-Oxigenase 2/metabolismo , Edema/tratamento farmacológico , Edema/induzido quimicamente , Ratos , Relação Estrutura-Atividade , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Estrutura Molecular , Acetatos/química , Acetatos/farmacologia , Acetatos/síntese química , Simulação de Acoplamento Molecular , Humanos , Relação Dose-Resposta a Droga , Formaldeído , Farmacóforo
6.
Mol Divers ; 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-39060857

RESUMO

Inspired from the important applications of spirocyclic compounds in medicinal chemistry, a new series of pyrazoline Spiro-oxindole tethered 1,2,3-triazole hybrids was reported via Cu(I)-catalyzed click reaction from isatin-pyrazoline linked terminal alkynes with in situ derived benzyl azides. Antimicrobial evaluation data showed that all hybrids exhibited promising efficacy towards the tested microbial strains. Antimicrobial screening as well as docking studies suggested that hybrid 6a was found to be most potent towards Aspergillus niger (MIC = 0.0122 µmol/mL) and Escherichia coli (MIC = 0.0061 µmol/mL). Molecular docking studies of 6a within the binding pockets of antibacterial and antifungal targets revealed good interactions with the binding energies of - 144.544 kcal/mol and - 154.364 kcal/mol against 1KZN (E. coli) and 3D3Z (A. niger), respectively. Further, MD simulations were performed to study the stability of the complexes formed at 300 K. Based on the RMSD trajectories, it is evident that 3D3Z-6a complex exhibits minimal deviation, whereas the 1KZN-6a complex displayed little more deviation compared to the protein but, both are in acceptable range. Moreover, 3D3Z-6a and 1KZN-6a showed maximum number of hydrogen bonds at 50 ns and 70 ns, respectively, thereby complementing the stability of these complexes.

7.
Mol Divers ; 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39083219

RESUMO

Helminthiasis, affecting billions globally, poses a significant health concern, especially in impoverished regions with inadequate sanitation. The intricate anatomical complexity of helminths requires specialized treatment approaches. There is currently no effective vaccine against helminth infections. Anthelmintics, crucial for combating these infections, target neuromuscular functions in parasites without harming the host. However, the emergence of resistance to existing anthelmintics, notably benzimidazoles, presents a growing global challenge. This review delves into the structure-activity relationship of previously synthesized core anthelmintic scaffolds-Benzimidazole, coumarin, pyrazoline, triazole, and others-to elucidate their promising anthelmintic activities. Understanding the structure-activity relationship of these novel benzimidazole derivatives, Coumarin derivatives, and others is crucial in designing potent anthelmintics, overcoming resistance, and optimizing efficacy to combat the escalating global burden of helminth infections. In the present review, we cover recently studied compounds (from the year 2019 to till date) which have promising anthelmintic activity. This review will be useful for the pharmacology and medicinal chemistry researchers working in the area anthelmintics with various scaffolds like aminobenzothiazole, benzimidazole, benzothiazole, coumarin, chromene, spiroketal, pyrazoline, triazole, etc. to design novel potent anthelmintic compound.

8.
Luminescence ; 39(6): e4811, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38924260

RESUMO

Water pollution has become a serious issue, and mercury(II) ion (Hg(II)) is highly toxic even at low concentrations. Therefore, Hg(II) concentration should be strictly monitored. This study evaluated pyrazoline compounds as fluorescence chemosensor agents for Hg(II) detection. These compounds were prepared from vanillin via etherification, Claisen-Schmidt, and cyclocondensation reactions, to yield benzothiazole-pyrazoline-styrene hybrid compounds. The hybrid compound without styrene was successfully synthesized in 97.70% yield with limit of detection (LoD) and limit of quantification (LoQ) values of 323.5 and 1078 µM, respectively. Conversely, the hybrid compound was produced in 97.29% yield with the LoD and LoQ values of 8.94 and 29.79 nM, respectively. Further spectroscopic investigations revealed that Hg(II) ions can either chelate with three nitrogen of pyridine, pyrazoline, and benzothiazole structures or two oxygen of vanillin and styrene. Furthermore, the hybrid compound was successfully applied in the direct quantification of Hg(II) ions in tap and underground water samples with a validity of 91.63% and 86.08%, respectively, compared with mercury analyzer measurement. The regeneration of pyrazoline was also easily achieved via the addition of an ethylenediaminetetraacetic acid solution. These findings show the promising application of the benzothiazole-pyrazoline-styrene hybrid compound for Hg(II) monitoring in real environmental samples.


Assuntos
Benzotiazóis , Corantes Fluorescentes , Limite de Detecção , Mercúrio , Pirazóis , Benzotiazóis/química , Pirazóis/química , Mercúrio/análise , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Estireno/química , Espectrometria de Fluorescência , Poluentes Químicos da Água/análise , Estrutura Molecular , Íons/análise
9.
Arch Pharm (Weinheim) ; 357(7): e2400081, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38548680

RESUMO

New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 µM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 µM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 µg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 µg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.


Assuntos
Antibacterianos , Antimaláricos , Antineoplásicos , Chalconas , Testes de Sensibilidade Microbiana , Plasmodium falciparum , Pirazóis , Piridinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Chalconas/farmacologia , Chalconas/síntese química , Chalconas/química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Antimaláricos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Animais , Relação Dose-Resposta a Droga , Neisseria gonorrhoeae/efeitos dos fármacos
10.
Int J Mol Sci ; 25(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39000394

RESUMO

A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.


Assuntos
Antineoplásicos , Hidroquinonas , Simulação de Acoplamento Molecular , Pirazóis , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Hidroquinonas/química , Hidroquinonas/farmacologia , Hidroquinonas/síntese química , Células MCF-7 , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Chalcona/farmacologia , Células HT29 , Chalconas/química , Chalconas/farmacologia , Chalconas/síntese química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Animais
11.
Bioorg Med Chem Lett ; 80: 129105, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36513215

RESUMO

The molecular hybridization of thiazole and pyrazoline heterocyclic structures with diverse activities appears to be an interesting strategy for developing new anticancer compounds. This study presents the synthesis of eleven new thiazolyl-pyrazoline derivatives (7a-k) and the evaluation of their in-vitro anti-proliferative activities against human lung carcinoma (A549) and human melanoma cancer (A375) cell lines through MTT assay. In comparison to the positive reference drug erlotinib (IC50 = 34.16 µM in A549 and IC50 = 25.85 µM in A375), four compounds (7e, 7h, 7j, and 7k) were identified as the most active against both cell lines (especially compound 7k with IC50 = 20.28 µM in A549 and 16.08 µM in A375). Additionally, these potent compounds were selected to be investigated for their anti-metastasis and anti-inflammatory properties via inhibition of the expression of matrix metalloproteinase 2, 9 (MMP-2, 9) and cyclooxygenase 2 (COX-2). In A549 cells, upon exposure to compounds 7e and 7j, COX-2 expression is decreased, whereas compounds 7e, 7j, and 7k reduced COX-2 expression in A375 cell lines. Molecular docking studies were carried out to show the possible interactions of synthesized compounds with the predicted active site of the COX-2 protein. The results revealed that compounds 7e and 7j can bind well to the active site of COX-2 protein. Collectively, compounds 7e, 7j, and 7k are all promising candidates for further research towards the development of novel anticancer agents.


Assuntos
Antineoplásicos , Metaloproteinase 2 da Matriz , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Metaloproteinase 2 da Matriz/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Antineoplásicos/química , Estrutura Molecular , Proliferação de Células , Linhagem Celular Tumoral
12.
J Fluoresc ; 2023 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-37740878

RESUMO

Utility of pyrazoles and their derivatives in constructing ordered porous materials with physicochemical characteristics such as chemosensors has undoubtedly created much interest in developing newer frameworks. A variety of pyrazole based chemosensors are known for their remarkable photophysical, pH sensitivity, solvatochromic, ion detection, high quantum yields and nonlinear optical behavior. Many of the transition metals have shown beneficial biological effects in biological systems. There is always a need of continuous monitoring to maintain an adequate range of all and specifically for the toxic ones like mercury. Pyrazoline nanoparticle probes have been reported for sensing/detection of Hg2+ions. Pyridinyl pyrazoline and benzimidazolyl pyrazole derived sensors are more selective and sensitive towards Zn2+and Fe3+ ions respectively. Pyrazole derived metal organic frameworks (MOF's) have been reported for environmental monitoring and biological imaging. Keeping in view of the enormous synthetic and biological importance of pyrazoles, herein, we are presenting an overview on applications of pyrazoles in transition metal chemosensors.

13.
J Fluoresc ; 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37646875

RESUMO

2-Pyrazoline containing benzothiazole ring 2-[1-(1,3-benzothiazol-2-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl]phenol (BP) have been synthesized for the effective identification of picric acid over other competing nitro compounds using fluorescence technique. The pyrazoline BP showed quenching efficiency as high as 82% comparative to other nitro aromatics. The limit of detection and limit of quantification were found to be 1.1 µM and 3.3 µM. The possible mechanism with the quenched PA detection efficiency was based on fluorescence energy transfer and photoinduced electron transfer. Moreover, the observed results were supported by the optimized structures of the compounds using the DFT/B3LYP/6-311G/LanL2DZ method. Eventually, the pyrazoline derivative BP was further utilized for natural water samples, showing recoveries in the 87.62-101.09% and RSD was less than 3%.

14.
Bioorg Chem ; 139: 106724, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37451146

RESUMO

Fragment merging approach was applied for the design of thiazole/thiazolidinone clubbed pyrazoline derivatives 5a-e, 6a-c, 7 and 10a-d as dual COX-2 and 5-LOX inhibitors. Compounds 5a, 6a, and 6b were the most potent and COX-2 selective inhibitors (IC50= 0.03-0.06 µM, SI = 282.7-472.9) with high activity against 5-LOX (IC50 = 4.36-4.86 µM), while compounds 5b and 10a were active and selective 5-LOX inhibitors with IC50 = 2.43 and 1.58 µM, respectively. In vivo assay and histopathological examination for most active candidate 6a revealed significant decrease in inflammation with higher safety profile in comparison to standard drugs. Compound 6a exhibited the same orientation and binding interactions as the reference COX-2 and 5-LOX inhibitors (celecoxib and quercetin, respectively). Consequently, compound 6a has been identified as a potential lead for further optimization and the development of safe and effective anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios , Tiazóis , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Fármacos , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/farmacologia , Tiazolidinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia
15.
Arch Pharm (Weinheim) ; 356(4): e2200562, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36599496

RESUMO

Carbonic anhydrase (CA) is a metalloenzyme that catalyzes the interconversion between carbon dioxide and water and dissociated ions of carbonic acid. In addition, CA performs various other functions in animals and plants, depending on the part of the living being. CAs have been found in almost all organisms. Besides, CAs are associated with several diseases, such as glaucoma, obesity, epilepsy, cancer, and so on. CAs are also involved in tumor cell growth and angiogenesis. Thus, inhibition of CA may be an attractive way of control of such diseases. Hence, CA inhibitors have been designed and developed to cure CA-associated diseases. Some examples of approved CA inhibitors are dorzolamide, methazolamide, brinzolamide, and dichlorphenamide. Furthermore, various heterocyclic scaffolds were utilized for the design of CA inhibitors. Among those, pyrazole/pyrazoline derivatives have exhibited greater potency toward CA inhibition. Hence, research that took place in the field of drug design and discovery of CA inhibition has been systematically reviewed and collated. Alongside, the structure-activity relationship has been described, followed by a description of the most potent molecules and their structural features.


Assuntos
Inibidores da Anidrase Carbônica , Farmacóforo , Pirazóis , Animais , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Neoplasias , Pirazóis/farmacologia , Pirazóis/química , Relação Estrutura-Atividade
16.
Int J Mol Sci ; 24(10)2023 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-37240450

RESUMO

Some new Bis-pyrazoline hybrids 8-17 with dual EGFR and BRAFV600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.


Assuntos
Antineoplásicos , Proliferação de Células , Teoria da Densidade Funcional , Desenho de Fármacos , Receptores ErbB , Proteínas Proto-Oncogênicas B-raf , Pirazóis , Humanos , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/toxicidade , Eletricidade Estática , Relação Estrutura-Atividade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade
17.
Int J Mol Sci ; 24(6)2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36982392

RESUMO

Multi-drug resistant bacterial strains (MDR) have become an increasing challenge to our health system, resulting in multiple classical antibiotics being clinically inactive today. As the de-novo development of effective antibiotics is a very costly and time-consuming process, alternative strategies such as the screening of natural and synthetic compound libraries is a simple approach towards finding new lead compounds. We thus report on the antimicrobial evaluation of a small collection of fourteen drug-like compounds featuring indazoles, pyrazoles and pyrazolines as key heterocyclic moieties whose synthesis was achieved in continuous flow mode. It was found that several compounds possessed significant antibacterial potency against clinical and MDR strains of the Staphylococcus and Enterococcus genera, with the lead compound (9) reaching MIC values of 4 µg/mL on those species. In addition, time killing experiments performed on compound 9 on Staphylococcus aureus MDR strains highlight its activity as bacteriostatic. Additional evaluations regarding the physiochemical and pharmacokinetic properties of the most active compounds are reported and showcased, promising drug-likeness, which warrants further explorations of the newly identified antimicrobial lead compound.


Assuntos
Anti-Infecciosos , Pirazóis , Pirazóis/farmacologia , Pirazóis/química , Indazóis/farmacologia , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana
18.
Molecules ; 28(18)2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37764362

RESUMO

A series of novel 3-cyanopyridone/pyrazoline hybrids (21-30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Relação Estrutura-Atividade , Proteínas Proto-Oncogênicas B-raf , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Proliferação de Células , Receptores ErbB/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia
19.
Molecules ; 28(21)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37959874

RESUMO

A new series of thiazolyl-pyrazoline derivatives (4a-d, 5a-d 6a, b, 7a-d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a-b). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC50 = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC50 = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC50 = 0.024, and 0.005 µM, respectively, whereas their IC50 = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC50 = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.


Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Lapatinib/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/química , Antineoplásicos/química , Proliferação de Células , Receptores ErbB/metabolismo , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral
20.
J Fluoresc ; 32(3): 835-862, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35199297

RESUMO

Disclosure of new molecular probes as chromogenic and fluorogenic cation sensors is scientifically exigent work. Recently chalcone derivatives gained more attention because of their structural variability. A suitable donor and acceptor groups separated by delocalized π-orbitals display excellent chromogenic and fluorogenic properties because of intramolecular charge transfer (ICT). These designed molecular frameworks provide the coordination sites to the incoming metal ions results in small changes in the optical properties. In a typical sensing behavior, coordination leads to a large conjugation plane with the probe resulted in hypo/hyperchromic shifts or red/blue shifts. In this review, we tried to converge the reported chalcone-derived sensors and explored the design, synthesis, metal ion sensing mechanism, and practical application of the probes. We expect that this review gives a basic outline for researchers to explore the field of chalcone-based sensors further.

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