RESUMEN

BACKGROUND: The Computer-Aided Drug Discovery (CADD) approach was used to develop a few Epidermal Growth Factor Receptor (EGFR) kinase inhibitors. EGFR kinase expression is highly associated with genomic instability, higher proliferation, lower hormone receptor levels, and HER2 over-expression. It is more common in breast cancer. Thus, EGFR Kinase is one of the main targets in discovering new cancer medicine. OBJECTIVE: To computationally validate some amides substituted ß-amino enones as EGFR inhibitors and to carry out associated in vitro anticancer agents. METHODS: We used tools such as molecular docking, MD simulations, DFT calculations, and ADMET predictions in silico to establish a preliminary SAR. In vitro, we used BT474 (ER+HER2+) and MCF-7 (ER-HER2) cell lines along with normal breast cell epithelial cells (MFC-10a) for anticancer studies and EGFR kinase inhibition assay studies. As the Reactive Oxygen Species (ROS) plays the main role in cancer development, we also analyzed the antioxidant potentials of these compounds. RESULTS: Among the family of eleven amides substituted (Z)-ß-amino enones (5a-k), compounds 5b, 5c, 5g, and 5h showed valuable in silico and in vitro bio-activity. Remarkably, the in-silico results almost coincided with in vitro study results. CONCLUSION: We recommend compounds 5b, 5c, 5g, and 5h for pre-clinical and clinical evaluation to establish them as future cancer therapeutics.

RESUMEN

The main objective of this study is to screen potential small molecule inhibitors against HPV (Human Papilloma Virus)-16 E6 protein (HPV16 E6P) using a fragment-based approach. Twenty-six natural HPV inhibitors were selected based on the review of the literature. Among them, Luteolin was selected as the reference compound. These 26 compounds were used to generate novel inhibitors against HPV16 E6P. Fragment script and BREED of Schrodinger software were used to build novel inhibitor molecules. The result in 817 novel molecules was docked into the active binding site of HPV E6 protein and the top ten compounds were screened based on binding affinity compared to Luteolin for further study. Compounds Cpd5, Cpd7, and Cpd10 were the most potent inhibitors of HPV16 E6P and these were non-toxic and showed high Gastrointestinal (GI) absorption and positive drug-likeness score. Complexes of these compounds were stable in the 200 ns Molecular Dynamics (MD) simulation. These 3 HPV16 E6P inhibitors could be the lead molecules as new drugs for HPV-related diseases.Communicated by Ramaswamy H. Sarma.

Asunto(s)

Simulación de Dinámica Molecular , Infecciones por Papillomavirus , Humanos , Luteolina , Sitios de Unión , Virus del Papiloma Humano , Simulación del Acoplamiento Molecular

RESUMEN

Cervical cancer is one of the major causes of death in women, especially in developing countries bearing more than a quarter of the global burden. Secreted phosphoprotein-1, also known as OPN (osteopontin), is an integrin-binding glycophosphoprotein that is overexpressed in a variety of tumors. OPN is a chemokine-like calcified ECM-associated protein that plays a crucial role in evaluating the metastatic potential of various cancers. However, the role of SPP1 in the tumor microenvironment and associated signaling pathways in CC is still unclear. In our study, three CC microarray datasets (GSE9750, GSE46857, and GSE67522) were obtained from the GEO database to identify the differentially expressed genes. Enrichment analysis was carried out by Enrichr and ShinyGO and the PPI interaction network was created by using String and Cytoscape. GEPIA datasets were used to validate the top 10 hub genes, and virtual screening, docking, and dynamic simulation studies were used to identify a suitable inhibitor against the OPN protein using MVD, PyRx, and GROMACS respectively. Our results show that a total of 11 DEGs were common for three datasets and gene ontology pathway enrichment analysis revealed that 2 biological processes i.e. programmed cell death and animal organ development commonly affected mechanisms in all three datasets. Docking and dynamic studies revealed that Entrectinib showed excellent binding affinity against OPN protein. Based on the results, we conclude that OPN is one of the most upregulated genes in cervical cancer and Entrectinib emerges to be a promising potential OPN inhibitor to curtail cervical cancer progression. Schematic representation: The schematic representation of methodology steps is illustrated in the graphical abstract. Schematic representation of methodology.

Asunto(s)

Osteopontina , Neoplasias del Cuello Uterino , Animales , Humanos , Femenino , Osteopontina/genética , Osteopontina/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Benzamidas , Perfilación de la Expresión Génica , Biología Computacional/métodos , Microambiente Tumoral

RESUMEN

BACKGROUND: Marine actinobacteria have proven to be a remarkable source of bioactive metabolites. METHODS: The present study focused on the isolation of anticancer metabolites from marine actinobacteria. Streptomyces sp. VITGAP173 was found to have promising anticancer activity against breast cancer cell lines (MCF-7). RESULTS: Bioassay-guided fractionation was followed to identify the bioactive metabolites from crude ethyl acetate extract of VITGAP173, which yielded four fractions. Among the four fractions, fraction B exhibited the highest cytotoxic activity against MCF-7 cell lines. Further structural characterization of the fraction was done by FTIR and NMR spectroscopy. The fraction-2 induced cytotoxicity against MCF-7 cell lines and the half maximal inhibition (IC50) value was calculated as 4.7µg/ml. To elucidate the possible mechanism of cell death, MCF-7 cells were treated with fraction-2 for 24 hours and the morphological changes were examined using acridine orange - ethidium bromide (AO/EB) staining. The fraction also increased the reactive oxygen species (ROS) generation (Flow cytometry, DCFH-DA). The molecular mechanism of fraction-induced cell death was analysed by real-time PCR, which revealed that the fraction promotes apoptosis through the CHOP-ATF-4 pathway which is involved in ER stress signalling. CONCLUSION: The present findings suggest the apoptosis inducing potential of fraction-2 in breast cancer therapy.

RESUMEN

Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.

Asunto(s)

Aterosclerosis/prevención & control , Colesterol/metabolismo , Células Espumosas/efectos de los fármacos , Lipoproteínas LDL/antagonistas & inhibidores , Fitoquímicos/uso terapéutico , Animales , Anticolesterolemiantes/química , Anticolesterolemiantes/uso terapéutico , Aterosclerosis/metabolismo , Células Espumosas/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Estructura Molecular , Fitoquímicos/química , Fitoterapia/métodos , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Plantas Medicinales/química

RESUMEN

PURPOSE: SARS-CoV-2 is a SARS-like novel coronavirus strain first identified in December 2019 in Wuhan, China. The virus has since spread globally, resulting in the current ongoing coronavirus disease 19 (COVID-19) pandemic. SARS-CoV-2 spike protein is a critical factor in the COVID-19 pathogenesis via interactions with the host cell angiotensin-converting enzyme 2 (ACE2) PD domain. Worldwide, numerous efforts are being made to combat COVID19. In the current study, we identified potential peptidomimetics against the SARS-CoV-2 spike protein. METHODS: We utilized the information from ACE2-SARS-CoV-2 binary interactions, and based on crucial interacting interface residues, novel peptidomimetics were designed. RESULTS: Top scoring peptidomimetics were found to bind at the ACE2 binding site of the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. CONCLUSIONS: The current studies could pave the way for further investigations of these novel and potent compounds against the SARS-CoV-2.

RESUMEN

OBJECTIVE: The objective of the study was to develop new Cyclooxygenase-2 inhibitors as anti-inflammatory agents from the synthetic route. MATERIALS AND METHODS: The 2-phenyl-4H-chromen-4-one and 2-phenyl-2,3-dihydro-4H-chromenone hybrids were synthesised and characterised by using UV, IR, 1H-NMR, and mass spectrometry. An attempt was made for consolidated lead flavones and flavanones scaffolds by determining ADME/ T properties. Molecular docking simulations were performed by using Autodock.4 to understand the binding interaction over the targeted enzyme Cyclooxygenase-2. The titled compounds were evaluated for various in-vitro models for antioxidant and anti-inflammatory activities and based upon the IC50 values, the selected compounds were screened for in vivo anti-inflammatory activity by both acute and chronic models. RESULTS AND DISCUSSION: Twenty titled compounds were synthesised and elucidated their structure for confirmation of their functional groups by various spectroscopic techniques. Among the synthesized compounds, flavone derivatives such as HFc (7-hydroxy-3-(4-methoxy phenyl)-4H-chromen-4- one), HFd (2-(2,4-di methoxy-phenyl)-7-hydroxy-4H-chromen-4-one) and HFe (7-hydroxy-2- (thiophen-2-yl)-4H-chromen-4-one) produced higher potency. Flavanone derivatives HFAc (7- hydroxy-2-(4-hydroxy-3-methoxy phenyl)-2,3-dihydro-4H-chromen-4-one), HFAb (7-hydroxy-2-(4- methoxy phenyl)-2,3-dihydro-4H-chromen-4-one) and HFAd (7-hydroxy-2-(thiophen-2-yl)-2,3- dihydro-4H-chromen-4-one) showed significant anti-inflammatory activity compared to the standard COX-2 inhibitors. CONCLUSION: The flavone and flavanone scaffolds possess their excellent inhibitory action over the Cyclooxygenase-2 and act as a potential anti-inflammatory agent. The results of computational studies were also significantly correlated and concluded that those naturally mimicking flavonoid analogues were tremendous candidates to fight against the inflammatory diseases in drug discovery.

Asunto(s)

Antiinflamatorios/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Flavanonas/farmacología , Flavonas/farmacología , Simulación del Acoplamiento Molecular , Antiinflamatorios/química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Flavanonas/química , Flavonas/química , Concentración 50 Inhibidora , Relación Estructura-Actividad

RESUMEN

With the rapid growth of the COVID-19 (coronavirus disease 2019) pandemic across the globe, therapeutic attention must be directed to fight the novel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). However, developing new antiviral drugs and vaccines is time-consuming, so one of the best solutions to tackle this virus at present is to repurpose ready-to-use drugs. This paper proposes the repurposing of the Food and Drug Administration (FDA)-approved, purchasable, and naturally occurring drugs for preventive and therapeutic use. We propose to design a dual-inhibitor for the SARS-CoV-2 cysteine proteases-3 Chemotrypsin-like protease or main protease (3CLpro or Mpro) and Papain-like protease (PLpro) responsible for processing the translated polyprotein chain from the viral RNA yielding functional viral proteins. For virtual screening, an unbiased blind docking was performed from which the top nine dual-targeting inhibitors for 3CLpro and PLpro were selected. The nine repurposed drugs, block the catalytic dyad (His41 and Cys145) of 3CLpro as well as the catalytic triad (Cys111, His272, and Asp286) of PLpro. Repurposing known drugs will not only pave the way for rapid in-vitro and in-vivo studies to battle the SARS-CoV-2 but will also expedite the quest for a potent anti-coronaviral drug.

RESUMEN

TRAF2 and NCK-interacting kinase (TNIK) is a critical factor in colorectal cancer (CRC) proliferation mediated by Wnt signaling. We attempted to identify efficient TNIK inhibitors using computational high-throughput virtual screening (HTVS) from various drug banks and databases. By performing/on performing e-pharmacophore screening and molecular docking methods, from ∼700 000 molecules, compounds LC_222150, LC_112060, and LC_64796 were identified as potential leads, through molecular dynamics (MD) simulations and density functional theory (DFT). These top 3 structures were commercially procured, and their inhibitory activity was assessed in vitro. Significant TNIK inhibition was observed, with an average IC50 of 18.33 ± 0.75 nM. In terms of anticancer activity, the observed average relative % activity (RPA) of 90.28 ± 1.04 for these compounds compared well with doxorubicin (86.75 ± 1.45) as a standard. Compounds LC_222150, LC_112060, and LC_64796, therefore, warrant further evaluation in vivo to assess their CRC therapeutic effects.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/química , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Oncogénicas/metabolismo , Inhibidores de Proteínas Quinasas/química , Factor 2 Asociado a Receptor de TNF/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Teoría Funcional de la Densidad , Doxorrubicina/farmacología , Doxorrubicina/normas , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Ensayos Analíticos de Alto Rendimiento , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Relación Estructura-Actividad

RESUMEN

BACKGROUND AND OBJECTIVE: Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection. METHODS: Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. RESULTS: We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus. CONCLUSION: Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.

Asunto(s)

Betacoronavirus/metabolismo , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Péptidos/farmacología , Neumonía Viral/prevención & control , Glicoproteína de la Espiga del Coronavirus/metabolismo , Enzima Convertidora de Angiotensina 2 , Antivirales/farmacología , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/virología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , SARS-CoV-2 , Vacunas Virales/farmacología

RESUMEN

BACKGROUND: Macrophages play a serious part in the instigation, upkeep, and resolution of inflammation. They are activated or deactivated during inflammation progression. Activation signals include cytokines (IF-γ, granulocyte-monocyte colonystimulating factor (GM-CSF), and TNF-α), extracellular matrix proteins, and other chemical mediators. Activated macrophages are deactivated by anti-inflammatory cytokines (IL- 10 and TGF-ß (transforming growth factor-beta) and cytokine antagonists that are mainly produced by macrophages. Based on this, the present study aimed to develop novel (E)- Benzylidene-indazolpyridin methanones (Cpd-1-10) as effective anti-inflammatory agents by analyzing pro- and anti-inflammatory cytokine levels in macrophages. OBJECTIVES: To determine the anti-inflammatory effect of indazolpyridin-methanones by examining pro- and anti-inflammatory interleukin levels in J77A.1 macrophages. METHODS: Expression of cytokines such as TNF-α, IL-1ß, IL-6 and IL-10 serum levels measured by ELISA method. Anti-cancer and cytotoxicity studies were carried out by MTT assay. COX-2 seems to be associated with cancers and atypical developments in the duodenal tract. So, a competitive ELISA based COX-2 inhibition assay was done. To validate the inhibitory potentials and to get more insight into the interaction of COX-2 with Cpd1-10, molecular docking was performed. RESULTS: Briefly, the COX-2 inhibitory relative activity was found to be in between the range of 80-92% (Diclofenac showed 84%, IC50 0.95 µM). CONCLUSION: Cytotoxicity effect of the compounds against breast cancer cell lines found excellent and an extended anticancer study ensured that these compounds are also alternative therapeutic agents against breast cancer. Among all the tested cancer cell lines, the anti- cancer effect on breast cancer was exceptional for the most active compounds Cpd5 and Cpd9.

Asunto(s)

Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Compuestos de Bencilideno/farmacología , Citocinas/metabolismo , Indazoles/farmacología , Macrófagos/efectos de los fármacos , Piridinas/farmacología , Animales , Antiinflamatorios/química , Antineoplásicos/química , Compuestos de Bencilideno/química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/química , Humanos , Indazoles/química , Macrófagos/metabolismo , Ratones , Simulación del Acoplamiento Molecular , Piridinas/química

RESUMEN

A series of new 1,2,4-triazole and 1,3,4-oxadiazole derivatives was obtained via several steps sequential reactions of phenyl piperazine. Then, these compounds were converted to the corresponding fluoroquinolone hybrids via one pot three component Mannich reaction. All the reactions were examined under conventional and microwave mediated conditions, and optimum conditions were determined. The effect of different solvents and microwave power on microwave prompted reactions was investigated as well. All the newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR and EI MS spectral techniques. The antimicrobial activity, DNA gyrase and Topoisomerase IV inhibition potentials were performed. The results obtained showed that fluoroquinolone hybrids possess good antimicrobial activity. Moreover, Fluoroquinolone-azole-piperazine hybrids synthesized in the present study displayed excellent DNA gyrase inhibition. To unveil the interaction mode of compounds to receptor, a molecular docking study was performed. With an average least binding energy of -9.5 kcal/mol, all compounds were found to have remarkable inhibitory potentials against DNA gyrase (E. coli).

Asunto(s)

Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Piperazinas/farmacología , Triazoles/farmacología , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/metabolismo , Enterococcus faecalis/efectos de los fármacos , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/metabolismo , Fluoroquinolonas/síntesis química , Fluoroquinolonas/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Microondas , Simulación del Acoplamiento Molecular , Piperazinas/síntesis química , Piperazinas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Triazoles/síntesis química , Triazoles/metabolismo

RESUMEN

Amide substituted (Z)-ß-enaminones were synthesized by green chemistry and stereo-specific synthetic pathway as novel phosphoinositide 3-kinase (PI3K) inhibitors and breast cancer drugs. PI3K inhibition was measured by competitive ELISA. A panel of cancer cell lines including MCF-7 (breast cancer), G-361 (skin cancer), and HCT 116 (colon cancer) were used to assess the anticancer potentials. In the PI3K assay, 2c and 2f were indolent for the proposed inhibitory action, which was recognized from the obtained IC50 (>1.0 µM). Excellent activity potential of 2a, 2b, and 2d was recognized from the IC50 range (<0.05 µM) whereas an intermediate action potential was observed for compounds 2e and 2i (IC50 0.1 and 0.25, respectively). The docking results exclusively proposed that the hydrophobic interactions in the PI3K binding pocket were overwhelmed by the binding affinity of the most potent ligands (2a, 2b, and 2d: inhibitory constant Ki = 18.16, 84.87, and 56.14 nM). MTT assay results revealed the antiproliferative activity domination of selected compounds (2a, 2b, and 2d) toward MCF-7. The relative activities of 2a, 2b, and 2d of 84.56, 80.87, and 90.12%, respectively, were comparable to that of the standard, doxorubicin (82.16%). SAR studies demonstrated amide substituted (Z)-ß-enaminones as precise PI3K inhibitors to treat breast cancer.

Asunto(s)

Amidas/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Amidas/síntesis química , Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

1,2,4-Triazole derivatives containing a piperazine nucleus (4a-d and 10) were prepared starting from 1-(2-methoxyphenyl)piperazine or ethyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate via several steps. The synthesis of fifteen compounds (7a-l and 13a-c), which can be considered as new analogues of azole class antifungals was performed starting from 1,2,4-triazoles (4a-d and 10) via three steps containing the condensation with 2-bromo-1-(4-chlorophenyl)ethanone, reduction of carbonyl group to alcohol and alkylation of OH group, respectively. All the reactions were examined under conventional, ultrasound and microwave irradiation conditions as green chemistry techniques, and optimum conditions were defined. The newly synthesized compounds were screened for their biological potentials including antimicrobial, antioxidant, antiurease and anti α-glucosidase activities and promising results were obtained. The enzyme inhibitory potentials of these compounds were further validated through molecular docking.

Asunto(s)

Antibacterianos/farmacología , Antifúngicos/farmacología , Antioxidantes/farmacología , Azoles/farmacología , Inhibidores Enzimáticos/farmacología , Microondas , Ondas Ultrasónicas , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Azoles/síntesis química , Azoles/química , Bacterias/efectos de los fármacos , Canavalia/enzimología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hongos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Ureasa/antagonistas & inhibidores , Ureasa/metabolismo , alfa-Glucosidasas/metabolismo

RESUMEN

AIM: Due to their effective binding affinity to receptors which are responsible for various diseases, benzimidazoles are often bioactive. Present study intended and carried out to synthesis, characterize and develop benzimidazole-based antiulcer drugs. Materials & methods: Established 8a-l were evaluated for gastric antisecretory/antiulcer properties using freshly prepared H+-K+-ATPase from goat fundus mucosa. Molecular docking was carried out to unveil best binding affinities with H+-K+-ATPase (protein data bank ID: 2XZB). RESULTS: The obtained least inhibitory constant of 8a-l (18-92 nM) was comparable to the in vitro H+-K+-ATPase inhibition (IC50: 24-122 nM). Furthermore, the lethal effect of 8a-l to colon cancerous cells and nonharm effect to the normal cells was recognized through cytotoxicity studies. CONCLUSION: After all in silico, in vitro experimental and structure-activity relationship predictions, the antiulcer druggability potential of 8a-l was recognized. A future drug development study for the most potent compounds among 8a-l is strongly indorsed.

Asunto(s)

Antiulcerosos/farmacología , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Ácido Gástrico/metabolismo , Úlcera Gástrica/tratamiento farmacológico , Antiulcerosos/síntesis química , Antiulcerosos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Developing a new antibacterial drug by using (Z/E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H)-diones (5a-h) via DNA gyrase inhibition mechanism is the main aim of this study. DNA gyrase inhibition assay was executed to confirm the DNA gyrase inhibition potentials of 5a-h. DNA gyrase inhibitory potentials were further validated through molecular docking. Docking study was also intended to get more insight into the binding mode of 5a-h into the active site of DNA gyrase A. Agar well diffusion method antimicrobial activity on Gram-ve bacteria Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram+ve bacteria (Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent DNA gyrase inhibition was exhibited by the compound 5c, IC50 0.55±0.12 µM; 5d, IC50 0.65±0.075 µg/mL; 5e, IC50 0.45±0.035 µM; 5f, IC50 0.58±0.025 µM; 5h, IC50 0.25±0.015 µM while Clorobiocin (standard) showed IC50 0.5±0.05 µM. Apart from all the in vitro studies, a plausible mechanism of DNA gyrase inhibition was also proposed through the in silico validations that are including molecular docking, predicted SAR, functional group availability, pharmacokinetic, and ADMET properties. These predictions are well supported to confirm the druggability possibility of the most potent compounds among (Z/E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H) -diones (5a-h).

Asunto(s)

Antibacterianos/química , Proteínas Bacterianas/química , Girasa de ADN/química , Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular/métodos , Inhibidores de Topoisomerasa II/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Compuestos de Bencilideno/química , Sitios de Unión , Girasa de ADN/metabolismo , Isoquinolinas/química , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Inhibidores de Topoisomerasa II/farmacología

RESUMEN

In this study, novel 3-O-methoxy-4-halo, disubstituted-5,7-dimethoxy chromans with bacterial cell wall degrading potentials were synthesized, characterized and evaluated as DNA gyrase inhibitors and antibacterial agents. Compounds were showed a broad spectrum of antimicrobial activity against both Gram+ve bacteria (S. aureus (MTCC 3160), C. diphtheriae (MTCC 116), S. pyogenes (MTCC 442)) and Gram-ve bacteria (E. coli (MTCC 443), P. aeruginosa (MTCC 424), K. pneumoniae (MTCC 530)). Further, a molecular docking study was carried out to get more insight into the binding mode of present study compounds to target proteins (PDB ID: 2XCT (S. aureus DNA gyrase A), PDB ID: 3G75 (S. aureus DNA gyrase B), PDB ID: 3L7L (Teichoic acid polymerase). In the results, 14 > 20 > 24 > 12 > 18 > 17 were found as the most active against almost all executed activities in this study. The predicted Lipinski's filter scores, SAR, pharmacokinetic/pharmacodynamics, and ADMET properties of these compounds envisioned the druggability prospects and the necessity of further animal model evaluations of 3-O-methoxy-4-halo disubstituted 5,7-dimethoxy chromans to establish them as an effective and future antibiotics.

Asunto(s)

Antibacterianos/química , Cromanos/química , Girasa de ADN/metabolismo , Inhibidores de Topoisomerasa II/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Cromanos/metabolismo , Cromanos/farmacología , Girasa de ADN/química , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacología

RESUMEN

N-substituted hydroxynaphthalene imino-oxindole derivatives (5a-g) were emerged as the inhibitors of the phosphoinositide 3-kinase (PI3K), which is a crucial regulator of apoptosis or programmed cell death. Electron donor-/acceptor-substituted indole-imine (5a-g) was achieved, and the structures were elucidated by FTIR, 1H NMR, 13C NMR and HRMS. Inhibition potency of PI3Ks was assessed by competitive ELISA. Subsequently, an anticancer activity against breast cancer (MCF-7) cell lines was evaluated. In both activities, compounds 5c, 5d and 5f showed most potent activities. Percentage inhibition for anticancer activity was 78.22 ± 1.02 (5c) and 78.98 ± 1.08 (5f), and the IC50 was 2.02 ± 0.92 µm (5c) and 1.98 ± 0.18 µm (5f). Compounds 5a and 5g were found inactive for both activities, and rest all showed a moderate activity. To get more insight into the binding mode and inhibitor binding affinity, 5a-g were docked into the active site of PI3Ks p110α (PDB ID: 2ENQ). Results suggested that the hydrophobic interactions in the binding pockets of PI3Ks conquered affinity of the most favourable binding ligands (5c and 5f: inhibitory constant (ki ) = 102.4 and 128.23 nm). The SAR studies demonstrate the efficiency of 5a-g as the PI3Ks precise inhibitors with the impending to treat various cancers.

Asunto(s)

Indoles/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Dominio Catalítico , Diseño de Fármacos , Femenino , Humanos , Iminas/química , Indoles/síntesis química , Indoles/metabolismo , Concentración 50 Inhibidora , Células MCF-7 , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-Actividad

RESUMEN

A series of 1-((2-hydroxynaphthalen-1-yl)(phenyl)(methyl))pyrrolidin-2-one derivatives by an efficient iodine catalyzed domino reaction involving various aromatic aldehydes, 2-pyrrolidinone and ß-naphthol was achieved and the structures were elucidated by FTIR 1H NMR, 13C NMR, and HRMS. Subsequently they were evaluated for cytotoxicity against breast cancer (MCF-7), colon cancer (HCT116) cell lines. In the cytotoxicity, the relative inhibition activity was remarkably found to be high in MCF-7 cell lines as 79% (4c), 83% (4f) and the IC50values were 1.03µM (4c), 0.98µM (4f). Compounds 4a, 4e, 4k-m, and 4q were found to be inactive and rest showed a moderate activity. In order to get more insight into the binding mode and inhibitor binding affinity, compounds (4a-q) were docked into the active site phosphoinositide 3-kinase (PI3K) (PDB ID: 4JPS) which is a crucial regulator of apoptosis or programmed cell death. Results suggested that the hydrophobic interactions in the binding pockets of PI3K exploited affinity of the most favourable binding ligands (4c and 4f: inhibitory constant (ki)=66.22nM and 107.39nM). The SAR studies demonstrated that the most potent compounds are 4c and 4f and can be developed into precise PI3K inhibitors with the capability to treat various cancers.

Asunto(s)

Antineoplásicos/síntesis química , Yodo/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirrolidinonas/química , Antineoplásicos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Sitios de Unión , Catálisis , Diseño de Fármacos , Células HCT116 , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Pirrolidinonas/síntesis química , Pirrolidinonas/toxicidad , Relación Estructura-Actividad

RESUMEN

PURPOSE: Substituted 2-(4-phenylquinolin-2-yl) phenols (PQPDs) emerged as the inhibitors of phosphoinositide 3-kinase (PI3K) and anticancer agents. METHOD: PI3K inhibition was assessed by competitive ELISA. Anticancer activity was evaluated against breast cancer (MCF-7), skin cancer (G-361), and colon cancer (HCT 116) cell lines. RESULTS: In PI3 Kinase assay, PQPDs 4c, 4d, and 4k were inactive with IC50 >5 µM. IC50 for 4a, 4b, 4f-h, and 4j was ≥0.05 µM. Rest PQPDs IC50 was <1.0 µM. Anticancer activity found selective toward breast cancer (MCF-7); 4a, 4b, and 4j were showed excellent inhibitory (73.95, 68.36, and 70.06%) and IC50 1.16 µM (4a), 2.07 µM (4b), 1.021 µM (4f) and 1.981 µM (4j) while the standard (Doxorubicin) found with IC50 1.812 µM (72% inhibition). PQPDs were docked into the active site of PI3 Kinase p110α (PDB ID: 2RD0). Docking results suggested the hydrophobic interactions in PI3K binding pocket conquered affinity of the most favorable binding ligands [4a, 4b: inhibitory constant (ki) = 53.33, 41.23 pM]. CONCLUSION: PI3K assay and cancer cell line experimental results ensured that the inhibitory and anticancer activity potentials of PQPDs are more selective toward breast cancer treatments. PQPDs 4a, 4b, 4f, 4g, and 4j were displayed potent PI3 Kinase and anticancer activities. SAR studies demonstrated PQPDs as the PI3K precise inhibitors with the impending to treat various cancers.

Asunto(s)

Antineoplásicos/farmacología , Fenoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Línea Celular Tumoral , Humanos , Simulación del Acoplamiento Molecular , Fenoles/química , Relación Estructura-Actividad