RESUMO
A series of 4-phenylcoumarin derivatives was synthesized and evaluated for their cellular anti-HIV-1 and HIV-2 activities as well as their inhibitory effects against HIV-1 reverse transcriptase (RT). The hydrazone compound 8b and the ethylthiosemicarbazide derivative 4c showed the best inhibition activity against wild-type (WT) HIV-1. The promising compounds were further evaluated against HIV-1 RT and exhibited significant inhibitory activity with compound 8b showing comparable effect to the reference NNRTI Efavirenz (IC50 = 9.01 nM). Structure activity relationship study revealed the importance of 6-chloro and 4-phenyl substituents for optimum activity, as well as the 5-atoms linker (=N-NH-CO-CH2-O-) at position 7 of coumarin scaffold that can support the rotation and flexibility of compound 8b to fit well in the binding pocket. The molecular docking of compound 8b demonstrated a typical seahorse binding mode with better binding interactions that covered more residues when compared to Efavirenz.
Assuntos
Fármacos Anti-HIV , HIV-1 , Simulação de Acoplamento Molecular , Inibidores da Transcriptase Reversa/química , Cumarínicos/farmacologia , Relação Estrutura-Atividade , Transcriptase Reversa do HIV , Desenho de Fármacos , Fármacos Anti-HIV/químicaRESUMO
Vulgarin, an eudesmanolide sesquiterpene isolated from Artemisia judaica, was refluxed with iodine to produce two derivatives (1 and 2), which were purified and spectroscopically identified as naproxen methyl ester analogs. The reaction mechanism by which 1 and 2 were formed is explained using a sigmatropic reaction with a 1,3 shift. The scaffold hopping via lactone ring opening enabled the new derivatives of vulgarin (1 and 2) to fit well inside the COX-2 active site with ΔG of -7.73 and -7.58 kcal/mol, respectively, which was better than that of naproxen (ΔG of -7.04 kcal/mol). Moreover, molecular dynamic simulations showed that 1 was able to achieve a faster steady-state equilibrium than naproxen. The novel derivative 1 showed promising cytotoxic activities against HepG-2, HCT-116, MCF-7, and A-549 cancer cell lines compared to those of vulgarin and naproxen.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Naproxeno/farmacologia , Linhagem Celular , Antineoplásicos/farmacologia , Ciclo-Oxigenase 2 , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
In a search for new neuropeptide S receptor antagonists, we have described a new series of quinolone-pyranopyrimidine hybrid derivatives aiming to modify the inhibitory characters towards NPSR to develop new therapeutic strategies against anxiety, addiction and food disorders. We identified six potent antagonists 3, 4b, 6, 8, 9 and 10 which counteracted the stimulatory effect of NPS at both Gq and Gs pathways, at low micromolar concentrations, through modulation of Ca2+ and cAMP signaling, respectively. Molecular docking predicted the orientation mode of the top active compounds; 10 and 4b with ΔG value of -23.94 and -23.87 kcal/mol, respectively that is considered good when compared to that of the reference compound ML154 (ΔG = -25.75 kcal/mol) . Molecular dynamic simulations confirmed the stability of binding of compound 10 to the homology model of NPSR as it reached the equilibrium after 4 ns at RMSD of 1.00 Å while ML154 was faster to achieve the equilibrium after 2 ns at RMSD of 1.00 Å.
Assuntos
Desenho de Fármacos , Quinolonas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
There is a continuous need in drug development approach for synthetic anticancer analogues with new therapeutic targets to diminish chemotherapeutic resistance of cancer cells. This study presents new group of synthetic thienopyrimidine analogues (1-9) aims as mGluR-1 inhibitors with anticancer activity. In-vitro antiproliferative assessment was carried out using viability assay against cancer cell lines (MCF-7, A-549 and PC-3) compared to WI-38 normal cell line. Analogues showed variable anticancer activity with IC50 ranging from 6.60 to 121 µg/mL with compound 7b is the most potent analogue against the three cancer cell lines (MCF-7; 6.57 ± 0.200, A-549; 6.31 ± 0.400, PC-3;7.39 ± 0.500 µg/mL) compared to Doxorubicin, 5-Flurouracil and Riluzole controls. Selected compounds were tested as mGluR-1 inhibitors in MCF-7 cell line and results revealed compound 7b induced significant reduction in extracellular glutamate release (IC50; 4.96 ± 0.700 µM) compared to other analogues and next to Riluzole (IC50; 2.80 ± 0.500 µM) of the same suggested mode of action. Furthermore, both cell cycle and apoptosis assays confirmed the potency of compound 7b for early apoptosis of MCF-7 at G2/M phase and apoptotic positive cell shift to (91.4%) compared to untreated control (19.6%) and Raptinal positive control (51.4%). On gene expression level, compound 7b induced over-expression of extrinsic (FasL, TNF-α and Casp-8), intrinsic (Cyt-C, Casp-3, Bax) apoptotic genes with down-regulation of anti-apoptotic Bcl-2 gene with boosted Bax/Bcl-2 ratio to 2.6-fold increase. Molecular docking and dynamic studies confirmed the biological potency through strong binding and stability modes of 7b where it was faster in reaching the equilibrium point and achieving the stability than Riluzole over 20 ns MD. These results suggest compound 7b as a promising mGluR inhibitory scaffold with anticancer activity that deserves further optimization and in-depth In-vivo and clinical investigations.
Assuntos
Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r2 = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best ΔG of -15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 Å after 3.5 ns, while flavopiridol did so at 0.5 Å after the same time (3.5 ns). 2b showed an IC50 of 0.0136 µM, 0.015 µM, and 0.054 µM against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC50 of 0.036 µM. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t. 131I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i. 131I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.
Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Descoberta de Drogas , Radioisótopos do Iodo/química , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Células A549 , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Células CHO , Morte Celular/efeitos dos fármacos , Cumarínicos/química , Cricetulus , Quinase 2 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Distribuição Tecidual/efeitos dos fármacosRESUMO
In this study, new pyrazolopyrimidine derivatives were designed and evaluated for anticancer activity. PIM-1 inhibitiory activity were measured for the most potent compounds. Molecular docking study and molecular dynamics were also done. Thus, the novel derivatives of pyrazolo[1,5-a]pyrimidine have been synthesized and characterized using different spectroscopic techniques. HMBC and NOESY experiments were used to confirm regiospecific structure of pyrimidine ring. The newly synthesized derivatives were evaluated for their antitumor activities against HCT-116 and MCF-7 cell lines. These derivatives showed clear in vitro antitumor activities. Compound 5h showed the highest bioactivity (IC50 = 1.51 µM) against HCT-116 cell line. While, compound 6c was the most potent derivative, its IC50 was 7.68 µM against MCF-7 cell line. Compounds 5c, 5g, 5h, 6a and 6c showed PIM-1 inhibitory activity with IC50 of 1.26, 0.95, 0.60, 1.82, 0.67, respectively µM that could be correlated with their cytotoxic effect. Molecular docking study was done to predict the mode of binding of the target compounds inside PIM-1 active site. The molecular dynamic simulation was conducted in order to evaluate stability of binding of the tested compounds.
Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazóis/química , Pirimidinas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Bisphosphonates are widely used for treatment of osteoporosis. Recently, they have been reported to be effective anticancer agents. In this work, we designed some substituted phenyl (azanediyl) bis (methylene phosphonic acid) to be tested for their anticancer effect. Both molecular docking and dynamics studies were used to select the top ranked highly scored compounds. The selected hits showed potential in vitro anticancer effect against some cell lines. Biodistribution pattern and gamma scintigraphy were conducted to the most effective derivative (BMBP) after radiolabeling with 99mTc. Results of biodistribution and scintigraphic imaging of 99mTc-BMBP in tumor bearing mice showed a notable tumor affinity, and confirmed the targeting affinity of BMBP to the tumor tissues. As a conclusion, BMBP could act as potential anticancer agent and imaging probe.
Assuntos
Adenocarcinoma Bronquioloalveolar/tratamento farmacológico , Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Imagem Óptica , Ácidos Fosforosos/farmacologia , Células A549 , Adenocarcinoma Bronquioloalveolar/diagnóstico por imagem , Adenocarcinoma Bronquioloalveolar/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Raios gama , Geraniltranstransferase/antagonistas & inibidores , Geraniltranstransferase/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Estrutura Molecular , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/química , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
l-Phosphinothricin (glufosinate or 2-amino-4-((hydroxy(methyl) phosphinyl) butyric acid ammonium salt (AHPB)), which is a structural analog of glutamate, is a recognized herbicide that acts on weeds through inhibition of glutamine synthetase. Due to the structural similarity between phosphinothricin and some bisphosphonates (BPs), this study focuses on investigating the possibility of repurposing phosphinothricin as a bisphosphonate analogue, particularly in two medicine-related activities: image probing and as an anti-cancer drug. As BP is a competitive inhibitor of human farnesyl pyrophosphate synthase (HFPPS), in silico molecular docking and dynamic simulations studies were established to evaluate the binding and stability of phosphinothricin with HFPPS, while the results showed good binding and stability in the active site of the enzyme in relation to alendronate. For the purpose of inspecting bone-tissue accumulation of phosphinothricin, a technetium (99mTc)-phosphinothricin complex was developed and its stability and tissue distribution were scrutinized. The radioactive complex showed rapid, high and sustained uptake into bone tissues. Finally, the cytotoxic activity of phosphinothricin was tested against breast and lung cancer cells, with the results indicating cytotoxic activity in relation to alendronate. All the above results provide support for the use of phosphinothricin as a potential anti-cancer drug and of its technetium complex as an imaging probe.
Assuntos
Aminobutiratos/química , Antineoplásicos/química , Reposicionamento de Medicamentos , Compostos Radiofarmacêuticos/química , Tecnécio/química , Alendronato/química , Aminobutiratos/farmacologia , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diagnóstico por Imagem , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Compostos Radiofarmacêuticos/farmacologia , Relação Estrutura-Atividade , Tecnécio/farmacologia , Distribuição TecidualRESUMO
A series of fused pyrroles were synthesized and tested for their in vivo anti-inflammatory activity. Among 14 examined derivatives, 5 derivatives (1b-e, g and 5b), showed a promising anti-inflammatory activity equivalent to reference anti-inflammatory drugs (indomethacin and ibuprofen). A molecular docking study was conducted to interpret the biological activities of the tested compounds. The docking results were complementary with the phase of the biological survey and confirmed the biological effects.
Assuntos
Anti-Inflamatórios/síntese química , Indóis/síntese química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Indóis/química , Indóis/farmacologia , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Hepatitis C virus (HCV) infection is highly persistent and presents an unmet medical need requiring more effective treatment options. This has spurred intensive efforts to discover novel anti-HCV agents. The RNA-dependent RNA polymerase (RdRp), NS5B of HCV, constitutes a selective target for drug discovery due to its absence in human cells; also, it is the centerpiece for viral replication. Here, we synthesized novel pyrrole, pyrrolo[2,3-d]pyrimidine and pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives. The non-toxic doses of these compounds on Huh 7.5 cell line were determined and their antiviral activity against HCVcc genotype 4a was examined. Compounds 7j, 7f, 5c, 12i and 12f showed significant anti HCV activity. The percent of reduction for the non-toxic doses of 7j, 7f, 5c, 12i and 12f were 90%, 76.7±5.8%, 73.3±5.8%, 70% and 63.3±5.8%, respectively. The activity of these compounds was interpreted by molecular docking against HCV NS5B polymerase enzyme.
Assuntos
Inibidores Enzimáticos/farmacologia , Purinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Purinas/químicaRESUMO
A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki=0.35-0.88nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki=3.26-23.45nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC50=0.21, 0.21 and 0.23nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R(2) of 0.81.
Assuntos
4-Hidroxicumarinas/farmacologia , Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , 4-Hidroxicumarinas/síntese química , 4-Hidroxicumarinas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/químicaRESUMO
UNLABELLED: Background. T-cell populations regulate the balance of immune responses. The CD (Cluster of differentiation) 4+CD25+ regulatory T cells (Tregs) are crucial for maintaining negative control of various immune responses. There are different T-cell subpopulations with regulatory functions, as natural killer T cells, CD8+ and CD28. The forkhead box P3 (FOXP3) regulates Treg development and is required for its suppressive function. AIM: To evaluate the hepatic expression of the intrahepatic Tregs, Ig (immunoglobulin) G and IgM plasma cells in autoimmune hepatitis (AIH) and other chronic liver diseases (CLDs). MATERIAL AND METHODS: This study included 100 pediatric patients; 50 AIH and 50 CLDs other than AIH. All patients were subjected to routine investigations of CLDs plus immune-staining of liver tissue for FOXp3, IgG and IgM plasma cells, CD4 and CD8 T-cells. RESULTS: The FOXP3+ T cells in patients with AIH (6.3 ± 5) were significantly higher than that in the non-AIH (2.1 ± 2.6). FOXP3+ T cells were abundant in liver tissue with marked inflammatory cellular infiltrate. CD4+ and CD8+ infiltrating the liver tissue and IgG positive cells were significantly higher in AIH group, while the expression of IgM positive cells showed no significant difference. The IgG/IgM was significantly higher in the AIH treatment responders (3 ± 3) than non-responders (1.6 ± 0.5), while there was no significant difference regarding the intrahepatic expression of FOXP3+, CD4+, CD8+ cells, T-cells, IgG and IgM plasma cells. CONCLUSION: Intrahepatic Tregs were increased in number in patients with AIH in the initial presentation, and their presence is associated with increased activity and inflammation in liver biopsy.
Assuntos
Hepatite Autoimune/imunologia , Fígado/imunologia , Linfócitos T Reguladores/imunologia , Fatores Etários , Anti-Inflamatórios/uso terapêutico , Biomarcadores/análise , Biópsia , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Fatores de Transcrição Forkhead/análise , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/patologia , Humanos , Imunoglobulina G/análise , Imunoglobulina M/análise , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Plasmócitos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do TratamentoRESUMO
Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 µM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results.
Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/prevenção & controle , Simulação de Acoplamento Molecular , Animais , Carragenina , Cumarínicos/toxicidade , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/toxicidade , Modelos Animais de Doenças , Desenho de Fármacos , Edema/induzido quimicamente , Indometacina/farmacologia , Masculino , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Ratos , Úlcera Gástrica/induzido quimicamenteRESUMO
Reactions of ethylidenethiocarbohydrazide with hydrazonoyl halides gave 1,3-thiazole or 1,3,4-thiadiazole derivatives according to the type of hydrazonoyl halides. Treatment of ethylidenethiosemicarbazide with hydrazonoyl halides and dimethylacetylene dicarboxylate (DMAD) afforded the corresponding arylazothiazoles and 1,3-thiazolidin-4-one derivatives, respectively. The structures of the synthesized products were confirmed by IR, ¹H-NMR, (13)C-NMR and mass spectral techniques. The cytotoxic activity of the selected products against the Hepatic carcinoma cell line (Hepg-2) was determined by MTT assay indicating a concentration dependent cellular growth inhibitory effect, especially for compounds 14c and 14e. The dose response curves indicated the IC50 (the concentration of test compounds required to kill 50% of cell population) were 0.54 µM and 0.50 µM, respectively. Confocal laser scanning imaging of the treated cells stained by Rhodamin 123 and Acridine orange dyes confirmed that the selected compounds inhibit the mitochondrial lactate dehydrogenase enzymes. The binding mode of the active compounds was interpreted by a molecular docking study. The obtained results revealed promising cytotoxic activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Tiazóis/químicaRESUMO
Malignant melanoma is the most invasive skin cancer with the highest risk of death. The inhibition of BRAFV600E appears relevant for overcoming secondary resistance developed during melanoma treatment. BRAFV600E triggers angiogenesis via modification of the expression of angiogenic inducers, which play a crucial role in the metastasis of melanoma. Accordingly, the dual inhibition of the BRAFV600E/VEGFR-2 signaling pathway is considered a rational approach in the design of anti-melanoma candidates. In this study, a new class of pyrazolylindolin-2-one linked coumarin derivatives as dual BRAFV600E/VEGFR-2 inhibitors targeting A375 melanoma cells was designed. Target compounds were tailored to occupy the pockets of BRAFV600E and VEGFR-2. Most of the synthesized compounds demonstrated potent mean growth inhibitory activity against A375 cells. Compound 4j was the most active cytotoxic derivative, displaying an IC50 value at a low micromolar concentration of 0.96 µM with a significant safety profile. Moreover, 4j showed dual potent inhibitory activity against BRAFV600E and VEGFR-2 (IC50 = 1.033 and 0.64 µM, respectively) and was more active than the reference drug sorafenib. Furthermore, derivative 4j caused significant G0/G1 cell cycle arrest, induced apoptosis, and inhibited the migration of melanoma cells. Molecular docking showed that compound 4j achieved the highest ΔG value of -9.5 kcal mol-1 against BRAFV600E and significant ΔG of -8.47 kcal mol-1 against VEGFR-2. Furthermore, the structure-activity relationship study revealed that TPSA directly contributed to the anticancer activity of the tested compounds.
RESUMO
OBJECTIVE: This study aimed to develop and implement a program-wide active learning framework to guide active learning and assessment efforts in an entry-to-practice competency-based Doctor of Pharmacy program. METHODS: The development of the framework involved 3 stages: creation of a framework aligned with the program's guiding principles, provision of training and support to faculty and students, and evaluation of the students' and academic staff satisfaction using an online survey over 2 academic years (2022-2023). Data from this survey were analyzed descriptively. RESULTS: An active learning framework that was aligned with the program's guiding principles while allowing flexibility for individual teaching styles was developed. It consisted of 4 stages: preclass preparation, in-class work, prelaboratory preparation, and in-laboratory activities (emphasizing knowledge acquisition and competency development). Academic staff surveys reported higher satisfaction of staff in year 2 than year 3 of the program, with indications of further training on specific modalities. Students' satisfaction improved from year 2 to 3, particularly, in areas related to class objectives, learning environment, and feedback. CONCLUSION: The transformation of a curriculum that includes the evolution of the teaching and learning strategy is a complex, long-term project that deserves continuing attention. Having frameworks in place helps the management, instructors, and students to understand the global direction, stay focused, and support the implementation of competency-based education and student-centered learning.
RESUMO
Molecular docking simulation study was carried out to design a novel series of spiro [(2H, 3H)quinazoline-2,1'-cyclohexan]-4(1H)-one derivatives as a new class of effective PARP-1 inhibitors. Spiro [2H-3,1-benzoxazine-2,1'-cyclohexan]-4(1H)-one (5) was the starting compound to synthesize the target proposed analogues. The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti-proliferative activity against the cultured human breast carcinoma cell line (MCF-7) using doxorubicin as a standard drug. Additionally, the compounds that exhibited the highest cytotoxic efficiency were further subjected to PARP-1 enzyme assay taking 3-aminobenzamide as the reference drug. The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Cicloexanos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Poli(ADP-Ribose) Polimerases , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Neoplasias da Mama/patologia , Proliferação de Células , Desenho Assistido por Computador , Cicloexanos/síntese química , Doxorrubicina/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Feminino , Humanos , Células MCF-7 , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/metabolismo , Conformação Proteica , Quinazolinas/síntese químicaRESUMO
Cyclin dependent kinases (CDKs) enzymes regulate cell proliferation and transcriptional processes and can be considered as important targets for the development of anticancer and antimicrobial drugs. In this work, novel benzothiazolyl pyrazolopyrimidine carboxamide and benzothiazolyl pyrazolopyrimidine carbonitrile derivatives were synthesized and characterized. The synthetic process was carried out via the reaction of ylidine benzothiazole derivatives with pyrazolocarboxamide and pyrazolocarbonitrile through a Michael addition pathway. Docking studies were done against CDK2 and CDK9 enzymes and revealed that compound 8a showed high free energy of binding against CDK2 (-8.10 kcal/mol) while compound 15a showed the highest free energy of binding against CDK2 (-8.16 kcal/mol) and CDK9 (-7.87 kcal/mol). Molecular dynamics simulations were conducted to compare the stability of binding of the most active compound 15a and the potent reference drugs roscovitine and dinaciclib. A CDK enzyme assay was done against CDK2 and CDK9 for the previously mentioned top-ranked compounds, 8a and 15a. It was found that compound 15a was the most potent inhibitor for both enzymes with IC50 of 127 ± 1.01 nM and 65 ± 0.50 nM. The anticancer activity of the synthesized compounds was also determined by NCI against 60 cell lines. Compound 8a showed the highest cytotoxic activity against a large number of the tested cell lines. The antimicrobial activity of the synthesized compounds was determined against various gram positive and gram-negative bacteria as well as fungi. The results showed that compound 15a had the strongest antibacterial activity.
Assuntos
Antineoplásicos , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases , Benzotiazóis/farmacologia , Antibacterianos/farmacologia , Proliferação de Células , Purinas/farmacologia , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
BACKGROUND: Nitrogenous bisphosphonates (NBPs) are the major class of drugs that are used to treat osteoporosis. Recently, bisphosphonates (BPs) were reported to have an anticancer effect. These agents feature a high affinity that enables them to bind strongly to the human farnesyl pyrophosphate synthase enzyme. The correlation between this affinity and their anticancer effect was confirmed. OBJECTIVE: To date, the use of an oxygen atom as an isosteric replacement for the electronegative nitrogen atom in NBPs has not been reported, and its ability to retain the linker length and bisphosphonate pharmacophore remains unknown. The main aim of this work was to design some isosteric bisphosphonate analogs with oxygen atoms and evaluation of their binding affinity and anticancer activity. METHODS: The binding mode and stability of the designed compounds were achieved using human farnesyl pyrophosphate synthase (HFPPS) by docking and dynamic simulations. The compounds were synthesized, characterized, and screened for their anticancer activity against the breast cancer MCF-7 cell line and lung cancer A-549 cell line. The inhibitory activity of the tested compounds against HFPPS was evaluated. RESULTS: The compounds under investigation showed potential anticancer activity against the lung cell line with IC50 values of 41.7, 47.4, and 34.8 µg/ml in comparison to that of Risedronic acid (115 µg/ml). However, they do not exhibit potential activity against the breast cancer cell line. CONCLUSION: Compounds VII and VIII showed in vitro inhibition of human farnesyl pyrophosphate synthase with IC50 values of 82.2 and 98.8 µg/ml, respectively. Further optimization may be required in the future.
Assuntos
Antineoplásicos , Difosfonatos , Humanos , Simulação de Acoplamento Molecular , Células MCF-7 , Antineoplásicos/farmacologia , Relação Estrutura-AtividadeRESUMO
The present work describes a quinazolinone-based lead optimization for the development of novel purine nucleoside phosphorylase (PNP) inhibitors with quinazolinone scaffold. Nineteen compounds were proposed and docked against PNP, the best 14 compounds with highest docking and affinity scores and low RMSD values were synthesized. Synthesis of new quinazolinone derivatives with variable acetamide substituents on two positions on quinazoline ring was performed. The structures assigned to the products were concordant with the microanalytical and spectral data. In vitro cytotoxicity on human breast cancer cell line (MCF7) was performed and identified compound 6g as the most potent with IC50 (0.99 ± 0.11 µM) which was further tested against five different breast cancer cell lines in addition to normal breast cell to determine the selectivity. Compound 6g was subjected to molecular dynamic simulation study, radiolabelling and biodistribution study to investigate its stability and selectivity toward breast cancers. The in vitro PNP inhibition results were aligned with the in silico, cytotoxicity, and biodistribution results where 6g showed the most potent PNP inhibitory activity with IC50 (0.159 ± 0.007 µM) when compared to Peldesine (BCX-34) IC50 (0.041 ± 0.002 µM).