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1.
Eur J Med Chem ; 197: 112280, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32361286

RESUMO

Herein, we demonstrate that butein (1) can prevent swelling in a murine lymphedema model by suppressing tumor necrosis factor α (TNF-α) production. Butein derivatives were synthesized and evaluated to identify compounds with in vitro anti-inflammatory activity. Among them, 20 µM of compounds 7j, 7m, and 14a showed 50% suppression of TNF-α production in mouse peritoneal macrophages after lipopolysaccharide stimulation. Compound 14a, exhibited the strongest potency with an in vitro IC50 of 14.6 µM and suppressed limb volume by 70% in a murine lymphedema model. The prodrug strategy enabled a six-fold increase in kinetic solubility of compound 1 and five-fold higher levels of active metabolite in the blood for compound 14a via oral administration in the pharmacokinetics study. We suggest that the compound 14a could be developed as a potential therapeutic agent targeting anti-inflammatory activity to alleviate lymphedema progression.


Assuntos
Anti-Inflamatórios/uso terapêutico , Chalconas/uso terapêutico , Linfedema/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Chalconas/síntese química , Chalconas/farmacocinética , Humanos , Lipopolissacarídeos/farmacologia , Linfedema/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Fator de Necrose Tumoral alfa/metabolismo
2.
Chem Biol Interact ; 324: 109084, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289290

RESUMO

INTRODUCTION: An imbalance between oxidants and antioxidants in favour of oxidants, potentially leading to damage, is termed oxidative stress. Antioxidants (AO), either enzymatic or non-enzymatic, are the ones that can reduce diverse effects of pro-oxidants such as DNA, proteins and lipids damage. Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. Aim of this study was to test antioxidative potency of 15 chalcones (Chs) in in vitro model in serum (native conditions), so as with exogenously induced oxidative stress. MATERIAL AND METHODS: Oxidative stress was induced in serum samples of healthy individuals with 0.25 mmol/L terc-buthyl-hydroperoxide (TBH), and then we monitored the effects of various concentrations of chalcones on oxidative stress parameters: total antioxidative status (TAS), total oxidative status (TOS), total concentration of sulfhydryl group (SHG) and prooxidative-antioxidative balance (PAB), and calculated prooxidative score, antioxidative score, and oxy score (OS). Nonparametric repeated measures ANOVA (Friedman's test) was used for comparison of antioxidative potency of samples with 15 different chalcones, in a native state and upon TBH influence. Spearman's nonparametric correlation analysis was used for estimation of relation between different parameters. RESULTS: Negative Oxy Score (OS) values for Chs11-15 showed significantly stronger antioxidative potency compared to other investigated chalcones (p < 0.05). Ch11, Ch13 and Ch14 remained with negative OS even after TBH addition, whereas OS of Ch12 and Ch15 became positive, with small nominal values. Samples with Ch11 and Ch13 showed significant negative correlation between TAS and TOS (p < 0.05 for both), but in Ch14 sample the negative correlation existed between TAS and PAB (p < 0.05). CONCLUSION: Lower value of OS (i.e. better antioxidative potency) was noticed in samples with Ch11-Ch15. Electron-donor effects of substituent groups as a structural part of these chalcones could explain its antioxidative capability. Phenolic and methyl groups are responsible for antioxidative ability enhancement of five chalcones with the best activity.


Assuntos
Antioxidantes/farmacologia , Sangue/metabolismo , Chalconas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/síntese química , Antioxidantes/química , Sangue/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , terc-Butil Hidroperóxido/farmacologia
3.
Eur J Med Chem ; 193: 112216, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208222

RESUMO

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 µM (IC50 = 6.4 µM) with the lowest cytotoxicity (IC50 > 80 µM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Chalconas/farmacologia , Desenvolvimento de Medicamentos , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/induzido quimicamente , Artrite/metabolismo , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Doença Crônica , Colágeno , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
4.
Curr Pharm Des ; 26(8): 802-814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32013827

RESUMO

BACKGROUND: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. OBJECTIVE: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. METHODS: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. RESULTS: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 µM, which is comparable with commercial product Darunavir. CONCLUSION: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.


Assuntos
Chalconas , Inibidores da Protease de HIV , Simulação de Acoplamento Molecular , Chalconas/síntese química , Chalconas/farmacologia , Protease de HIV , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Relação Estrutura-Atividade
5.
J Antibiot (Tokyo) ; 73(5): 299-308, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31988484

RESUMO

The swift spread of infections caused by drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), has quickly become a worldwide concern as infections spread from healthcare settings to the wider community. While ferrocenyl chalcones, which are chalcone derivatives with antimicrobial activity, have gained attention from researchers, further study is needed to assess their cytotoxicity. Ten newly developed chalcones, in which ring A was replaced with a ferrocenyl moiety and ring B contained increasing alkyl chain lengths from 1 to 10 carbons, were assessed. Using twofold broth microdilution, the minimum inhibitory concentration (MIC) of five of the ten compounds were lower against Gram-positive organisms (MICs from 0.008 mg ml-1 to 0.063 mg ml-1) than Gram-negative organisms (MICs = 0.125 mg ml-1). These novel ferrocenyl chalcone compounds were effective against three types of clinically isolated drug-resistant S. aureus, including an MRSA, and against other non-resistant clinically isolated and laboratory-adapted Gram-positive bacteria. The same compounds inhibited growth in non-resistant bacteria by potentially obstructing cellular respiration in Gram-positive bacteria. Images obtained through scanning electron microscopy revealed fully lysed bacterial cells once exposed to a selected compound that showed activity. The results indicate that these newly developed compounds could be important antimicrobial agents in the treatment of infections from clinically resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Chalconas/farmacologia , Compostos Ferrosos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Metalocenos/química , Antibacterianos/síntese química , Antibacterianos/química , Chalconas/síntese química , Chalconas/química , Farmacorresistência Bacteriana , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Relação Estrutura-Atividade
6.
Cell Biochem Biophys ; 78(1): 65-76, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31707583

RESUMO

Esophageal cancer is one of the malignant cancers with a low 5-year survival rate. Licochalcone (LC) H, a chemically synthesized substance, is a regioisomer of LCC extracted from licorice. The purpose of this study was to determine whether LCH might have anticancer effect on human esophageal squamous cell carcinoma (ESCC) cell lines via apoptosis signaling pathway. After 48 h of treatment, IC50 of LCH in KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510 cells were 15, 14, 18, 15, and 16 µM, respectively. This study demonstrated that LCH potently suppressed proliferation of ESCC cells in a concentration- and time-dependent manner. LCH triggered G2/M-phase arrest by modulating expression levels of cdc2, cyclin B1, p21, and p27. LCH also induced apoptosis of ESCC cells through reactive oxygen species-mediated endoplasmic reticulum (ER) stress via JNK/p38 activation pathways. The anticancer effect of LCH was associated with ER stress and mitochondrial dysfunction. It also affected protein levels of Mcl-1, tBid, Bax, Bcl-2, cytochrome c, Apaf-1, PARP, cleaved-PARP, and ER stress-related proteins (GRP78 and CHOP). Our findings provide the first demonstration that LCH has anticancer effect on ESCC. Thus, LCH might have potential for preventing and/or treating human ESCC.


Assuntos
Apoptose , Chalconas/química , Glycyrrhiza/química , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/isolamento & purificação , Chalconas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glycyrrhiza/metabolismo , Humanos , Janus Quinases/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Eur J Med Chem ; 187: 111980, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877539

RESUMO

Chalcones, containing an α,ß-unsaturated ketone fragment, are an important pharmacologically active agents because of their diverse mechanisms. This review provides an update on the recent developments (2009-2019.3) in the antibacterial activity of natural and synthetic chalcones. Moreover, the structure-activity relationships and mechanisms are also carefully summarized which will provide some important guidance for design and synthesis in future. This comprehensive and critical review will be helpful for medicinal chemists to develop more candidate antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Chalconas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Chalconas/síntese química , Chalconas/química , Química Farmacêutica , Humanos , Testes de Sensibilidade Microbiana
8.
Med Chem ; 16(2): 212-228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31146672

RESUMO

BACKGROUND: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. OBJECTIVES: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. METHODS: Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). RESULTS: Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. CONCLUSION: Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2.


Assuntos
Benzopiranos/química , Ácidos Borônicos/química , Chalconas/síntese química , Chalconas/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Chalconas/química , Chalconas/metabolismo , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Relação Estrutura-Atividade
9.
Molecules ; 25(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878304

RESUMO

The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-ß (Aß) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil (15a-15f) or 1,4-chalcone-donepezil (16a-16f) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aß peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N-biotinylated Aß(1-42) oligomers. We also demonstrate that the Aß binding site of these hybrids differs from that of Pittsburgh Compound B (PIB).


Assuntos
Peptídeos beta-Amiloides/metabolismo , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/efeitos dos fármacos , Compostos de Anilina/química , Butirilcolinesterase/metabolismo , Chalconas/síntese química , Chalconas/química , Donepezila/síntese química , Donepezila/química , Humanos , Modelos Moleculares , Tiazóis/química , Trítio/metabolismo
10.
Malar J ; 18(1): 421, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842914

RESUMO

BACKGROUND: Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. Plant derived synthetic pharmaceutical compounds are found to be a foremost research to obtain diverse range of potent leads. Amongst them, the chalcone scaffold is a functional template for drug discovery. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production. METHODS: The chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl benzaldehydes (or indole-3-carboxaldehyde) and were screened for anti-malarial activity by WHO Mark III schizont maturation inhibition assay. The cytotoxicity profile of a HeLa cell line was evaluated through MTT viability assay and the selectivity index (SI) was calculated. Haemozoin inhibition assay was performed to illustrate mode of action on a Plasmodium falciparum strain. RESULTS: The IC50 values of all compounds were in the range 0.10-0.40 µg/mL for MRC-2 (a chloroquine sensitive strain) and 0.14-0.55 µg/mL for RKL-9 (a chloroquine resistant strain) of P. falciparum. All the chalcones showed low cellular toxicity with minimal haemolysis. The statistically significant reduction (p < 0.05) in the haemozoin production suggests a similar mechanism than that of chloroquine. CONCLUSIONS: Out of ten chalcones, number 7 was found to be a lead compound with the highest potency (IC50 = 0.11 µg/mL), as compared to licochalcone (IC50 = 1.43 µg/mL) and with high selectivity index of 85.05.


Assuntos
Antimaláricos/farmacologia , Chalconas/farmacologia , Eritrócitos/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Descoberta de Drogas , Células HeLa , Hemeproteínas/antagonistas & inibidores , Hemólise/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Plantas
11.
Molecules ; 24(22)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731596

RESUMO

A series of 18 aminochalcone derivatives were obtained in yields of 21.5-88.6% by applying the classical Claisen-Schmidt reaction. Compounds 4-9, 14 and 16-18 with 4-ethyl, 4-carboxy-, 4-benzyloxy- and 4-benzyloxy-3-methoxy groups were novel, not previously described in the scientific literature. To determine the biological properties of the synthesized compounds, anticancer and antimicrobial activity assays were performed. Antiproliferative potential was evaluated on four different human colon cancer cell lines-HT-29, LS180, LoVo and LoVo/DX -using the SRB assay and compared with green monkey kidney fibroblasts COS7. Anticancer activity was described as the IC50 value. The best results were observed for 2'-aminochalcone (1), 3'-aminochalcone (2) and 4'-aminochalcone (3) (IC50 = 1.43-1.98 µg·mL-1) against the HT-29 cell line and for amino-nitrochalcones 10-12 (IC50 = 2.77-3.42 µg·mL-1) against the LoVo and LoVo/DX cell lines. Moreover, the antimicrobial activity of all derivatives was evaluated on two strains of bacteria: Escherichia coli ATCC10536 and Staphylococcus aureus DSM799, the yeast strain Candida albicans DSM1386 and three strains of fungi: Alternaria alternata CBS1526, Fusarium linii KB-F1 and Aspergillus niger DSM1957. In the case of E. coli ATCC10536 almost all derivatives hindered the bacterial growth (∆OD = 0). Furthermore, the best results were observed in the presence of 4'-aminochalcone (3), that completely limited the growth of all tested strains at the concentration range of 0.25-0.5 mg·mL-1. The strongest bacteriostatic activity was exhibited by novel 3'-amino-4-benzyloxychalcone (14), that prevented the growth of E. coli ATCC10536 with MIC = 0.0625 mg·mL-1.


Assuntos
Anti-Infecciosos , Antineoplásicos , Chalconas , Escherichia coli/crescimento & desenvolvimento , Fungos/crescimento & desenvolvimento , Neoplasias , Staphylococcus aureus/crescimento & desenvolvimento , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Células COS , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Chlorocebus aethiops , Células HT29 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia
12.
Bioorg Med Chem ; 27(22): 115123, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31623971

RESUMO

Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC50 values of 8.93 ±â€¯0.21 and 6.88 ±â€¯0.42 µM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.


Assuntos
Carbazóis/química , Carbazóis/síntese química , Chalconas/química , Chalconas/síntese química , Urease/antagonistas & inibidores , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
13.
Immunopharmacol Immunotoxicol ; 41(6): 568-576, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31594421

RESUMO

Purpose: Chalcones are precursors of flavonoids with a wide range of pharmacological activities. This study evaluates the anti-inflammatory effect of indole based chalcone derivative (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9) on lipopolysaccharide (LPS) activated murine macrophages RAW264.7 cells and carrageenan-induced acute model in rats.Materials and methods: LPS-treated RAW264.7 cell lines and carrageenan-induced animal model were employed to evaluate the anti-inflammatory activity of IC9. The cell cytotoxicity studies were carried out by MTT assay. Reactive oxygen species (ROS) production and other inflammatory markers such as prostaglandin E2 (PGE2), nitric oxide (NO) as well as cyclooxygenase-2 (COX-2) activity were determined using ELISA. The RT-PCR was performed to determine mRNA expressions in the case of inducible nitric oxide synthase (iNOS), COX-2, Toll-like receptor-4 (TLR-4) and also nuclear translocation of NF-κB activity.Results: LPS-activated RAW264.7 cells showed an increased level of ROS generation and other inflammatory markers such as PGE2, NO level and COX-2 activity. Expression of iNOS, COX- 2 and TLR-4 mRNA expression were also up-regulated along with nuclear translocation of NF-κB. On IC9 supplementation, all the above parameters of LPS-activated cells were found to be reversed, resembling the control group. Moreover, IC9 significantly inhibited paw swelling and exhibited maximum inhibition of 78.45% at low dose of 7.5 mg/kg.bwt.Conclusions: The targeting anti-inflammatory efficacy and profound NF-κB sensitive transcriptional regulatory mechanism of IC9 accounts for its effective anti-inflammatory action.


Assuntos
Anti-Inflamatórios , Chalconas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Carragenina/toxicidade , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Células RAW 264.7 , Ratos , Ratos Wistar
14.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500191

RESUMO

Numerous reports have shown that conjugated benzimidazole derivatives possess various kinds of biological activities, including anticancer properties. In this report, we designed and synthesized 24 new molecules comprising a benzimidazole ring, arene, and alkyl chain-bearing cyclic moieties. The results showed that the N-substituted benzimidazole derivatives bearing an alkyl chain and a nitrogen-containing 5- or 6-membered ring enhanced the cytotoxic effects on human breast adenocarcinoma (MCF-7) and human ovarian carcinoma (OVCAR-3) cell lines. Among the 24 synthesized compounds, (2E)-1-(1-(3-morpholinopropyl)-1H-benzimidazol-2 -yl)-3-phenyl-2-propen-1-one) (23a) reduced the proliferation of MCF-7 and OVCAR-3 cell lines demonstrating superior outcomes to those of cisplatin.


Assuntos
Benzimidazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 182: 111637, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494471

RESUMO

Natural products like coumarins, chalcones, and resveratrol have inherent biological activity in several models of diseases; therefore, their natural dimeric forms are highlighted in this review and their key structural similarities, isolation and pharmacological significance is discussed. These natural products may be dimerized during their biosynthesis, which proceeds through atom- and energy-sufficient methods involving dimeric enzymes, to provide complex structures from simple compounds. Coumarin-derived dimers features the C-C or C-O-C biaryl, terpene sidechain linkages or by cyclobutane ring and acts as inhibitors of α-glucosidase, and cytochrome p450 while some show anti-inflammatory and anti-viral activities, while chalcone-derived dimers have the 1,3-dihydroxy phenyl (resorcinol) substitution on the periphery of cyclobutane or cyclohexane ring and inhibit topoisomerase, protein tyrosine phosphatase 1B (PTP1B), and cathepsins and others possess anti-cancer, anti-inflammatory, and anti-plasmodial activities. Resveratrol-derived dimers have the resorcinol structure and are formed by oxidative coupling showing antioxidant, neuroprotective, anti-HIV, anti-tyrosinase, and cytotoxic activity. Bioavailability evidence of closely related structural monomers could be applicable to their dimeric forms. Application of bioisosteric principles to such dimeric compounds is also discussed. Overall, these dimeric natural products can provide potent templates for the natural product-based drug discovery against several diseases.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , DNA Topoisomerases/metabolismo , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Dimerização , Humanos , Estrutura Molecular , Resveratrol/síntese química , Resveratrol/química , Resveratrol/farmacologia , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
16.
Theranostics ; 9(18): 5183-5199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410209

RESUMO

Mesoporous silica nanoparticles (MSNs) are extensively used in bone tissue regeneration and local drug delivery. However, the effects of MSNs alone on osteoclast formation and function, as well as the utilization of MSNs to deliver natural molecules against bone resorption, remain unexplored. Here, we report the development of licorice-derived bioactive flavonoid isoliquiritigenin (ISL)-encapsulated MSNs (MSNs-ISL) as a potent bone-bioresponsive nanoencapsulation system for prevention of osteoclast-mediated bone loss in vitro and in vivo. Methods: We synthesized MSNs-ISL and then investigated the drug loading and release characteristics of the resulting nanoparticles. In vitro experiments on osteoclast differentiation and bone resorption were performed using mouse primary bone marrow-derived macrophages (BMMs). In vivo animal experiments were conducted using a lipopolysaccharide (LPS)-mediated calvarial bone erosion model. Results: The resulting MSNs-ISL were spherical and highly monodispersed; they possessed a large specific surface area and superior biocompatibility, and allowed acid-sensitive sustained drug release. Compared with free ISL and MSNs alone, MSNs-ISL significantly and additively inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast generation, decreased the size and quantity of sealing zones, and reduced the osteolytic capacity of osteoclasts in vitro. MSNs-ISL treatment also downregulated RANKL-stimulated mRNA expression of osteoclast-associated genes and transcription factors. Mechanistically, MSNs-ISL remarkably attenuated the RANKL-initiated expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylation of mitogen-activated protein kinases (MAPKs), and phosphorylation and degradation of inhibitor of κBα (IκBα), together with the nuclear translocation of nuclear factor-κB (NF-κB) p65 and the activator protein (AP)-1 component c-Fos. Moreover, MSNs-ISL almost completely restrained the expression of nuclear factor of activated T cells (NFATc1). Consistent with the in vitro results, MSNs-ISL could block osteoclast activity; relieve inflammation-related calvarial bone destruction in vivo; and suppress c-Fos, NFATc1, and cathepsin K expression levels. Conclusion: Licorice ISL-encapsulated MSNs exhibit notable anti-osteoclastogenetic effects and protect against inflammatory bone destruction. Our findings reveal the feasibility of applying MSNs-ISL as an effective natural product-based bone-bioresponsive nanoencapsulation system to prevent osteoclast-mediated bone loss.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Chalconas/uso terapêutico , Glycyrrhiza/química , Nanopartículas/química , Osteoclastos/patologia , Dióxido de Silício/química , Actinas/metabolismo , Animais , Reabsorção Óssea/patologia , Chalconas/síntese química , Chalconas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nanopartículas/ultraestrutura , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Porosidade , Ligante RANK/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Crânio/patologia
17.
Bioorg Med Chem ; 27(19): 115014, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31358358

RESUMO

A new series of 1,3-diketone, heterocyclic and α,ß-unsaturated derivatives were synthesized and evaluated for their AhR antagonist activity using zebrafish and mammalian cells. Compounds 1b, 2c, 3b and 5b showed significant AhR antagonist activity in a transgenic zebrafish model. Among them, compound 3b, and 5b were found to have excellent AhR antagonist activity with IC50 of 3.36 nM and 8.3 nM in a luciferase reporter gene assay. In stem cell proliferation assay, compound 5b elicited marked HSC expansion.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Chalconas/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Proteínas de Peixe-Zebra/antagonistas & inibidores , Animais , Células COS , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chlorocebus aethiops , Humanos , Células-Tronco/efeitos dos fármacos , Peixe-Zebra
18.
Eur J Med Chem ; 180: 350-366, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325783

RESUMO

Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Chalconas/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
19.
Bioorg Chem ; 90: 103034, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31280015

RESUMO

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20-89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.


Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/química , Chalconas/química , Inibidores da Colinesterase/química , Acetilcolinesterase/química , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Domínio Catalítico , Chalconas/síntese química , Chalconas/metabolismo , Chalconas/farmacocinética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Ensaios Enzimáticos , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Ondas Ultrassônicas
20.
Eur J Med Chem ; 178: 726-739, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229875

RESUMO

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aß1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 µM and 1.2 µM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 µM and 3.7 µM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aß1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aß1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Chalconas/síntese química , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
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