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1.
Artigo em Inglês | MEDLINE | ID: mdl-38828869

RESUMO

BACKGROUND: Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moiety as celecoxib, and lonazolac as COX-II inhibitors. AIMS: We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately. METHODS: Purified and characterized pyrazoles have been analyzed for in-vivo analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies. RESULTS: The ADME profile of synthesized compounds was found to be satisfactory. CONCLUSION: The synthesized compounds can serve as lead for further drug designing.


Assuntos
Analgésicos , Anti-Inflamatórios , Simulação de Acoplamento Molecular , Pirazóis , Pirazóis/farmacologia , Pirazóis/química , Animais , Analgésicos/farmacologia , Analgésicos/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Masculino , Camundongos , Relação Estrutura-Atividade , Edema/tratamento farmacológico , Edema/induzido quimicamente , Humanos , Ratos , Dor/tratamento farmacológico , Ratos Wistar
2.
Drug Dev Res ; 85(4): e22217, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38845214

RESUMO

As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Inflamatórios , Anti-Hipertensivos , Inibidores de Ciclo-Oxigenase 2 , Pirazóis , Tetrazóis , Pirazóis/farmacologia , Pirazóis/química , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/química , Anti-Hipertensivos/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/síntese química , Tetrazóis/farmacologia , Tetrazóis/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Ratos , Desenho de Fármacos , Masculino , Antifibróticos/farmacologia , Antifibróticos/química , Ciclo-Oxigenase 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Humanos , Peptidil Dipeptidase A/metabolismo
3.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731916

RESUMO

Herein, we report a series of 1,3-diarylpyrazoles that are analogues of compound 26/HIT 8. We previously identified this molecule as a 'hit' during a high-throughput screening campaign for autophagy inducers. A variety of synthetic strategies were utilized to modify the 1,3-diarylpyrazole core at its 1-, 3-, and 4-position. Compounds were assessed in vitro to identify their cytotoxicity properties. Of note, several compounds in the series displayed relevant cytotoxicity, which warrants scrutiny while interpreting biological activities that have been reported for structurally related molecules. In addition, antiparasitic activities were recorded against a range of human-infective protozoa, including Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania infantum. The most interesting compounds displayed low micromolar whole-cell potencies against individual or several parasitic species, while lacking cytotoxicity against human cells.


Assuntos
Pirazóis , Trypanosoma cruzi , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Humanos , Trypanosoma cruzi/efeitos dos fármacos , Antiparasitários/farmacologia , Antiparasitários/síntese química , Antiparasitários/química , Desenho de Fármacos , Leishmania infantum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química
4.
J Enzyme Inhib Med Chem ; 39(1): 2343352, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38700244

RESUMO

In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.


Assuntos
Antineoplásicos , Apoptose , Neoplasias da Mama , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sulfonamidas , Triazinas , Humanos , Triazinas/farmacologia , Triazinas/química , Triazinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/química , Sulfonamidas/síntese química , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células Tumorais Cultivadas , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Feminino , Linhagem Celular Tumoral , Esferoides Celulares/efeitos dos fármacos
5.
Pak J Pharm Sci ; 37(1(Special)): 173-184, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38747267

RESUMO

Hydrazones 1-6, azo-pyrazoles 7-9 and azo-pyrimidines 10-15 are compounds that exhibit antibacterial activity. The mode of action and structures of these derivatives have been previously confirmed as antibacterial. In this investigation, biological screening and molecular docking studies were performed for derivatives 1-15, with compounds 2, 7, 8, 14 and 15 yielding the best energy scores (from -20.7986 to -10.5302 kcal/mol). Drug-likeness and in silico ADME prediction for the most potent derivatives, 2, 7, 8, 14 and 15, were predicted (from 84.46 to 96.85%). The latter compounds showed good recorded physicochemical properties and pharmacokinetics. Compound 8 demonstrated the strongest inhibition, which was similar to the positive control (eflornithine) against Trypanosoma brucei brucei (WT), with an EC50 of 25.12 and 22.52µM, respectively. Moreover, compound 14 exhibited the best activity against Leishmania mexicana promastigotes and Leishmania major promastigotes (EC50 =46.85; 40.78µM, respectively).


Assuntos
Simulação de Acoplamento Molecular , Pirazóis , Pirimidinas , Tripanossomicidas , Trypanosoma brucei brucei , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Trypanosoma brucei brucei/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Leishmania mexicana/efeitos dos fármacos , Leishmania major/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Simulação por Computador , Compostos Azo/farmacologia , Compostos Azo/química , Compostos Azo/síntese química , Relação Estrutura-Atividade , Testes de Sensibilidade Parasitária
6.
Pak J Pharm Sci ; 37(1(Special)): 191-197, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38747269

RESUMO

synthesis of a pyrazole containing compound was achieved by reacting phenyl hydrazine with (E)-2-((4-bromophenyl) diazinyl)-1-phenylbutane-1,3-dione to produce 4-((4-bromophenyl) diazinyl)-5-methyl-1,3-diphenyl-pyrazole and characterization using mass spectrometer, 1H NMR and 13C NMR. The pharmacological evaluation of the synthesized compound, denoted as (KA5), against Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 29213 and Clostridiums sporogeneses ATCC 19404, indicate that there is no promising antibacterial activity. However, KA5 shows a competitive anticancer activity (IC50: 8.5µM) upon its evaluation against hepatocellular carcinoma cell line (HepG 2) compared to sorafenib (IC50: 4.51µM). Moreover, human skin fibroblast (HSF) was used to investigate the effect of KA5 on normal cell lines, (IC50: 5.53µM). The presented biological evaluations resulted in better understanding of structure-activity relationship for 1, 3, 4-trisubstituted pyrazoles and revealed a great opportunity for more investigations for novel pyrazole-containing anticancer agents.


Assuntos
Antibacterianos , Antineoplásicos , Pirazóis , Pirazóis/farmacologia , Pirazóis/síntese química , Pirazóis/química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Células Hep G2 , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Sorafenibe/farmacologia , Fibroblastos/efeitos dos fármacos , Niacinamida/farmacologia , Niacinamida/análogos & derivados , Niacinamida/síntese química , Niacinamida/química , Pseudomonas aeruginosa/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos
7.
Int J Mol Sci ; 25(10)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38791130

RESUMO

The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K2CO3 or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs.


Assuntos
Antifúngicos , Candida , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Candida/efeitos dos fármacos , Humanos , Oxazóis/química , Oxazóis/farmacologia , Oxazóis/síntese química , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Simulação por Computador , SARS-CoV-2/efeitos dos fármacos
8.
Int J Mol Sci ; 25(10)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38791418

RESUMO

In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1H-pyrazole-4-carboxylate (named GeGe-3) has emerged as a potential anticancer compound. GeGe-3 displays potent anti-angiogenic properties through the presumptive targeting of the protein kinase DMPK1 and the Ca2+-binding protein calreticulin. We further explored the anticancer potential of GeGe-3 on a range of established cancer cell lines, including PC3 (prostate adenocarcinoma), SKMEL-28 (cutaneous melanoma), SKOV-3 (ovarian adenocarcinoma), Hep-G2 (hepatocellular carcinoma), MDA-MB231, SKBR3, MCF7 (breast adenocarcinoma), A549 (lung carcinoma), and HeLa (cervix epithelioid carcinoma). At concentrations in the range of 10 µM, GeGe-3 significantly restricted cell proliferation and metabolism. GeGe-3 also reduced PC3 cell migration in a standard wound closure and trans-well assay. Together, these results confirm the anticancer potential of GeGe-3 and underline the need for more detailed pre-clinical investigations into its molecular targets and mechanisms of action.


Assuntos
Antineoplásicos , Movimento Celular , Proliferação de Células , Pirazóis , Humanos , Pirazóis/farmacologia , Pirazóis/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ureia/farmacologia , Ureia/química , Ureia/análogos & derivados
9.
Bioorg Chem ; 147: 107413, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38696844

RESUMO

Cyclin-dependent kinase 2 (CDK2) is a vital protein for controlling cell cycle progression that is critically associated with various malignancies and its inhibition could offer a convenient therapeutic approach in designing anticancer remedies. Consequently, this study aimed to design and synthesize new CDK2 inhibitors featuring roscovitine as a template model. The purine ring of roscovitine was bioisosterically replaced with the pyrazolo[3,4-d]pyrimidine scaffold, in addition to some modifications in the side chains. A preliminary molecular docking study for the target chemotypes in the CDK2 binding domain revealed their ability to accomplish similar binding patterns and interactions to that of the lead compound roscovitine. Afterwards, synthesis of the new derivatives was accomplished. Then, the initial anticancer screening at a single dose by the NCI revealed that compounds 7a, 9c, 11c, 17a and 17b achieved the highest GI% values reaching up to 150 % indicating their remarkable activity. These derivatives were subsequently selected to undertake five-dose testing, where compounds 7a, 9c, 11c and 17a unveiled the most pronounced activity against almost the full panel with GI50 ranges; 1.41-28.2, 0.116-2.39, 0.578-60.6 and 1.75-42.4 µM, respectively and full panel GI50 (MG-MID); 8.24, 0.6, 2.46 and 6.84 µM, respectively. CDK2 inhibition assay presented compounds 7a and 9c as the most potent inhibitors with IC50 values of 0.262 and 0.281 µM, respectively which are nearly 2.4 folds higher than the reference ligand roscovitine (IC50 = 0.641 µM). Besides, flow cytometric analysis on the most susceptible and safe cell lines depicted that 7a caused cell cycle arrest at G1/S phase in renal cancer cell line (RXF393) while 9c led to cell growth arrest at S phase in breast cancer cell line (T-47D) along with pronounced apoptotic induction in the mentioned cell lines. These findings afforded new anticancer pyrazolo[3,4-d]pyrimidine, roscovitine analogs, acting via CDK2 inhibition.


Assuntos
Antineoplásicos , Proliferação de Células , Quinase 2 Dependente de Ciclina , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Roscovitina , Humanos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Roscovitina/farmacologia , Roscovitina/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Linhagem Celular Tumoral , Purinas/farmacologia , Purinas/química , Purinas/síntese química
10.
Int J Mol Sci ; 25(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731825

RESUMO

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.


Assuntos
Amidas , Antineoplásicos , Antioxidantes , Proliferação de Células , Hidrazonas , Pirazóis , Humanos , Pirazóis/química , Pirazóis/farmacologia , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Antioxidantes/farmacologia , Antioxidantes/química , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Células MCF-7 , Células HeLa
11.
J Agric Food Chem ; 72(20): 11308-11320, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38720452

RESUMO

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 µg/mL that was superior to that of the agricultural fungicide boscalid (2.2 µg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 µM that was superior to that of boscalid (7.9 µM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Fungicidas Industriais , Oximas , Pirazóis , Succinato Desidrogenase , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/química , Succinato Desidrogenase/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/química , Fungicidas Industriais/síntese química , Relação Estrutura-Atividade , Oximas/química , Oximas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Proteínas Fúngicas/química , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Simulação de Acoplamento Molecular , Rhizoctonia/efeitos dos fármacos , Éteres/química , Éteres/farmacologia , Estrutura Molecular
12.
J Agric Food Chem ; 72(21): 11949-11957, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38757770

RESUMO

As the first marketed phenylpyrazole insecticide, fipronil exhibited remarkable broad-spectrum insecticidal activity. However, it poses a significant threat to aquatic organisms and bees due to its high toxicity. Herein, 35 phenylpyrazole derivatives containing a trifluoroethylthio group on the 4 position of the pyrazole ring were designed and synthesized. The predicted physicochemical properties of all of the compounds were within a reasonable range. The biological assay results revealed that compound 7 showed 69.7% lethality against Aedes albopictus (A. albopictus) at the concentration of 0.125 mg/L. Compounds 7, 7g, 8d, and 10j showed superior insecticidal activity for the control of Plutella xylostella (P. xylostella). Notably, compound 7 showed similar insecticidal activity against Aphis craccivora (A. craccivora) compared with fipronil. Potential surface calculation and molecular docking suggested that different lipophilicity and binding models to the Musca domestica (M. domestica) gamma-aminobutyric acid receptors may be responsible for the decreased activity of the tested derivatives. Toxicity tests indicated that compound 8d (LC50 = 14.28 mg/L) induced obviously 14-fold lower toxicity than fipronil (LC50 = 1.05 mg/L) on embryonic-juvenile zebrafish development.


Assuntos
Aedes , Desenho de Fármacos , Moscas Domésticas , Inseticidas , Simulação de Acoplamento Molecular , Pirazóis , Animais , Inseticidas/química , Inseticidas/síntese química , Inseticidas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Aedes/efeitos dos fármacos , Aedes/crescimento & desenvolvimento , Relação Estrutura-Atividade , Moscas Domésticas/efeitos dos fármacos , Moscas Domésticas/crescimento & desenvolvimento , Afídeos/efeitos dos fármacos , Afídeos/crescimento & desenvolvimento , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Estrutura Molecular , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Peixe-Zebra/embriologia
13.
Molecules ; 29(10)2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38792163

RESUMO

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1-4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4). All new derivatives 1-4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents.


Assuntos
Antineoplásicos , Antioxidantes , Pirazóis , Humanos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antioxidantes/farmacologia , Antioxidantes/química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular
14.
Bioorg Med Chem Lett ; 108: 129813, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38788964

RESUMO

Succinate dehydrogenase inhibitors are essential fungicides used in agriculture. To explore new pyrazole-carboxamides with high fungicidal activity, a series of N-substitutedphenyl-3-di/trifluoromethyl-1-methyl-1H-pyrazole-4-carboxamides bearing a branched alkyl ether moiety were designed and synthesized. The in vitro bioassay indicated that some target compounds displayed appreciable fungicidal activity. For example, compounds 5d and 5e showed high efficacy against S. sclerotiorum with EC50 values of 3.26 and 1.52 µg/mL respectively, and also exhibited excellent efficacy against R. solani with EC50 values of 0.27 and 0.06 µg/mL respectively, which were comparable or superior to penflufen. The further in vivo bioassay on cucumber leaves demonstrated that 5e provided strong protective activity of 94.3 % against S. sclerotiorum at 100 µg/mL, comparable to penflufen (99.1 %). Cytotoxicity assessment against human renal cell lines (239A cell) revealed that 5e had low cytotoxicity within the median effective concentrations. Docking study of 5e with succinate dehydrogenase illustrated that R-5e formed one hydrogen bond and two π-π stacking interactions with amino acid residues of target enzyme, while S-5e formed only one π-π stacking interaction with amino acid residue. This study provides a valuable reference for the design of new succinate dehydrogenase inhibitor.


Assuntos
Fungicidas Industriais , Simulação de Acoplamento Molecular , Pirazóis , Succinato Desidrogenase , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Humanos , Relação Estrutura-Atividade , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Succinato Desidrogenase/antagonistas & inibidores , Succinato Desidrogenase/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ascomicetos/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Relação Dose-Resposta a Droga , Éteres/química , Éteres/farmacologia , Éteres/síntese química , Rhizoctonia
15.
Bioorg Chem ; 148: 107424, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38728908

RESUMO

Pyrazolopyrimidine derivatives, including pyrazolopyrimidines, 6-aminopyrazolopyrimidines, 6-[(formyloxy)methyl]pyrazolopyrimidines, 6-(hydroxymethyl)pyrazolopyrimidine, and 6-(aminomethyl)pyrazolopyrimidines have been successfully prepared and tested against NCI-H226, NPC-TW01, and Jurkat cancer cell lines. Among the tested pyrazolopyrimidine compounds, we found 6-aminopyrazolopyrimidines and 6-(aminomethyl)pyrazolopyrimidines with essential o-ClPh or p-ClPh substituted moieties on N-1 pyrazole ring exhibited the best IC50 inhibition activity for Jurkat cells. Furthermore, optimization of the SAR study on the C-6 position of pyrazolopyrimidine ring demonstrated that 6-(N-substituted-methyl)pyrazolopyrimidines 17b, 17d, and 19d possessed the significant IC50 inhibitory activity for the different leukemia cell lines, especially for Jurkat, K-562, and HL-60. On the other hand, further SAR inhibition and docking model studies revealed that compound 19d, which has a 3-(1H-imidazol-1-yl)propan-1-amino side-chain on the C-6 position, was able to form four hydrogen bonds with residues Ala226, Leu152, and Glu194 and specifically extended into the P1 pocket subsite with Aurora A, resulting in improved inhibitory activity almost similar to SNS-314. To explore the anti-cancer mechanism, compound 19d was measured by Western blot analysis in Jurkat T-cells, however, it showed non-responsibility to Aurora B. For the further structural modifications on the lateral chain of compound 19d, compounds 24 with longer lateral chain were designed and synthesized for testing leukemia cell lines. However, compounds 24 was significantly decrease inhibition potency against leukemia cell lines. Based on the in-vitro results, compounds 17b and 19d could be considered to be the best potential lead drug in our study for the development of new and effective therapies for leukemia treatment. On the other hand, the DHFR inhibition results indicated compound 19d possessed good inhibitory activity and better than the reported naphthalene derivative. Through further comparisons of the model superposition of three-dimensional (3D) conformations in DHFR, compound 19d presented a similar structural alignment to Methotrexate and the reported naphthalene derivative and led to similar drug-like functional relationships. As a results, compound 19d would be a potential DHFR inhibitor for anti-leukemia drug candidate.


Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pirazóis , Pirimidinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Simulação de Acoplamento Molecular , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Leucemia/tratamento farmacológico , Leucemia/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química
16.
J Agric Food Chem ; 72(22): 12469-12477, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38771932

RESUMO

Photopharmacology can be implemented in a way of regulating drug activities by light-controlling the molecular configuations. Three photochromic ligands (PCLs) that bind on one or two sites of GABARs and nAChRs were reported here. These multiphoton PCLs, including FIP-AB-FIP, IMI-AB-FIP, and IMI-AB-IMI, are constructed with an azobenzene (AB) bridge that covalently connects two fipronil (FIP) and imidacloprid (IMI) molecules. Interestingly, the three PCLs as well as FIP and IMI showed great insecticidal activities against Aedes albopictus larvae and Aphis craccivora. IMI-AB-FIP in both trans/cis isomers can be reversibly interconverted depending on light, accompanied by insecticidal activity decrease or increase by 1.5-2.3 folds. In addition, IMI-AB-FIP displayed synergistic effects against A. craccivora (LC50, IMI-AB-FIP = 14.84-22.10 µM, LC50, IMI-AB-IMI = 210.52-266.63 µM, LC50, and FIP-AB-FIP = 36.25-51.04 µM), mainly resulting from a conceivable reason for simultaneous targeting on both GABARs and nAChRs. Furthermore, modulations of wiggler-swimming behaviors and cockroach neuron function were conducted and the results indirectly demonstrated the ligand-receptor interactions. In other words, real-time regulations of receptors and insect behaviors can be spatiotemporally achieved by our two-photon PCLs using light.


Assuntos
Aedes , Compostos Azo , Inseticidas , Neonicotinoides , Nitrocompostos , Pirazóis , Animais , Nitrocompostos/química , Nitrocompostos/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Compostos Azo/química , Compostos Azo/farmacologia , Neonicotinoides/química , Neonicotinoides/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Aedes/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Comportamento Animal/efeitos dos fármacos , Luz , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Receptores de GABA/metabolismo , Receptores de GABA/química
17.
Metallomics ; 16(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38802123

RESUMO

New binuclear copper(II) [Cu(II)] tetraligand complexes (six examples) with sulfanylpyrazole ligands were synthesized. Electron spin resonance (ESR) studies have shown that in solution the complexes are transformed to the mononuclear one. Fungicidal properties against Candida albicans were found for the Cu complexes with benzyl and phenyl substituents. An in vitro evaluation of the cytotoxic properties of Cu chelates against HEK293, Jurkat, MCF-7, and THP-1 cells identified the Cu complex with the cyclohexylsulfanyl substituent in the pyrazole core as the lead compound, whereas the Cu complex without a sulfur atom in the pyrazole ligand had virtually no cytotoxic or fungicidal activity. The lead Cu(II) complex was more active than cisplatin. Effect of the S-containing Cu complex on apoptosis and cell cycle distribution has been investigated as well.


Assuntos
Antifúngicos , Candida albicans , Complexos de Coordenação , Cobre , Pirazóis , Cobre/química , Cobre/farmacologia , Humanos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Ligantes , Candida albicans/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/síntese química , Cristalografia por Raios X , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Citostáticos/farmacologia , Citostáticos/química , Citostáticos/síntese química
18.
J Am Chem Soc ; 146(19): 13317-13325, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38700457

RESUMO

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Nitrilas , Pirazóis , Pirimidinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Apoptose/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Linhagem Celular Tumoral , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/síntese química , Rutênio/química , Rutênio/farmacologia , Luz , Estrutura Molecular , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo
19.
Luminescence ; 39(5): e4760, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38738510

RESUMO

The present communication reports on the synthesis of a novel methyl-pyridone azo fluorescent tag (MPAFT) were proven through 1H (NMR), FT-IR, UV-vis, and high-resolution mass spectrometry. The quantum chemical parameters of MPAFT were evaluated using density functional theory (DFT) analysis. It was further investigated for its latent fingerprint (LFPs) in various surfaces and anticounterfeiting applications. By exposing Level I-Level III, ridge features to UV light with a wavelength of 365 nm, a bioimaging investigation has also demonstrated the potential of MPAFT's emission behaviour. The cyclic voltammetry (CV) and linear sweep voltammetry (LSV) at MPAFT/MGCE (modified glassy carbon electrode) were used to explore the electrochemical sensitivity and reliable detection of dopamine (DA) in neutral PBS (pH 7) electrolyte solution, and the results show good sensitivity and detection. The lower detection limit for LSV was 0.81 µM under optimum conditions.


Assuntos
Dopamina , Técnicas Eletroquímicas , Corantes Fluorescentes , Pirazóis , Piridonas , Piridonas/química , Dopamina/análise , Dopamina/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Pirazóis/química , Humanos , Estrutura Molecular , Teoria da Densidade Funcional , Imagem Óptica , Processos Fotoquímicos
20.
Bioorg Chem ; 147: 107403, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38691909

RESUMO

A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI50 values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).


Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Inibidores de Proteínas Quinases , Pirazóis , Tioureia , Ureia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Tioureia/farmacologia , Tioureia/química , Tioureia/síntese química , Estrutura Molecular , Ureia/farmacologia , Ureia/química , Ureia/análogos & derivados , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/síntese química
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