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1.
J Biomol Struct Dyn ; : 1-11, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31411551

RESUMO

This study describes in silico designing of aptamers against the influenza virus using Monte Carlo method. Aptamers are short, single-stranded oligonucleotides and these bind to an ample range of biologically important proteins which are related to many disease conditions. The affinities and specificities of aptamers are comparable to antibodies. In the medicinal chemistry, quantitative structure-activity relationship (QSAR) is an important skill which is used for drug design and development. To study the inhibitory activity of aptamers, we have developed QSAR models based on Monte Carlo method. The nucleobase sequence descriptors Bk, BBk and BBBk are used to generate the QSAR models. A number of statistical benchmarks together with index of ideality of correlation (IIC) is considered to validate the build QSAR models. Data set of 98 aptamers is divided into four random splits. The statistical criteria R2 = 0.8711 and CCC = 0.9207 of the validation set of split 3 are best, so the build QSAR model of split 3 is the paramount model. The aptamer fragment responsible for the promotors of endpoint increase and decrease are also determined. These fragments are applied to design new nine aptamers from the lead aptamer APT01. Communicated by Ramaswamy H. Sarma.

2.
Artigo em Inglês | MEDLINE | ID: mdl-30652652

RESUMO

A series of 1-{2-(prop-2-ynyloxy)aryl}-3-hydroxy-3-(4'-trifluoromethyl-phenyl)prop-2-en-1-ones obtained by photo-irradiation of 2-{2-(prop-2-ynyloxy)benzoyl}-3-(4-trifluoromethyl-phenyl)oxiranes (that were characterized by spectral studies: FT-IR, 1H NMR, 13C NMR and Mass analysis) was screened for the anti-malarial activity by evaluating against chloroquine-sensitive P. falciparum (CD7). The molecular docking studies using AutoDock Vina were also performed to further ascertain the efficacy of these compounds with PDB:4ORM. Among these, the hydroxyenone derivatives 2b, 2c and 2a exhibited very potent anti-malarial activity that was clearly evinced by the results of molecular docking. Binding energies of hydroxyenone compounds were calculated and found in the range of -10.4 to -9.0 kcal/mol. Compound 2b had the strongest binding affinity with docking score of -10.4 kcal/mol.

3.
Sci Rep ; 8(1): 12743, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143692

RESUMO

Mitochondrial pathology has been implicated in the pathogenesis of psychotic disorders. A few studies have proposed reduced leukocyte mitochondrial DNA (mtDNA) copy number in schizophrenia and bipolar disorder type I, compared to healthy controls. However, it is unknown if mtDNA copy number alteration is driven by psychosis, comorbidity or treatment. Whole blood mtDNA copy number was determined in 594 psychosis patients and corrected for platelet to leukocyte count ratio (mtDNAcnres). The dependence of mtDNAcnres on clinical profile, metabolic comorbidity and antipsychotic drug exposure was assessed. mtDNAcnres was reduced with age (ß = -0.210, p < 0.001), use of clozapine (ß = -0.110,p = 0.012) and risperidone (ß = -0.109,p = 0.014), dependent on prescribed dosage (p = 0.006 and p = 0.026, respectively), and the proportion of life on treatment (p = 0.006). Clozapine (p = 0.0005) and risperidone (p = 0.0126) had a reducing effect on the mtDNA copy number also in stem cell-derived human neurons in vitro at therapeutic plasma levels. For patients not on these drugs, psychosis severity had an effect (ß = -0.129, p = 0.017), similar to age (ß = -0.159, p = 0.003) and LDL (ß = -0.119, p = 0.029) on whole blood mtDNAcnres. Further research is required to determine if mtDNAcnres reflects any psychosis-intrinsic mitochondrial changes.

4.
Drug Res (Stuttg) ; 2018 Jul 23.
Artigo em Alemão | MEDLINE | ID: mdl-30036888

RESUMO

Human farnesyl pyrophosphate synthase (hFPPS) is a well-settled therapeutic target and it is an enzyme of the mevalonate pathway which catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate. QSAR studies by using Monte Carlo method for human farnesyl pyrophosphate synthase inhibitors has been carried out using balance of correlation technique with Index of ideality correlation. For construction of QSAR models, six random splits were prepared from the data of 73 phosphonates and hybrid optimal descriptors procured from graph (HFG) and SMILES based notations were employed. The developed QSAR models have robustness, good fitting ability, generalizability and internal predictive ability. The external predictive ability has been certified by testing various precedents. The values of R2, IIC, Q2 and ∆R2m for the best model are 0.9304, 0.9614, 0.9061 and 0.0861 respectively. The developed QSAR models met with the specified standards given in OECD guideline and applicability domain. The structural feature promoters for the end point increase and promoters for end point decrease have been extracted. The predicted pIC50 for the new proposed compounds have also been reported.

5.
Chem Cent J ; 12(1): 9, 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29411150

RESUMO

After publication of the original article [1], the following error was reported in the Results section of the Abstract: "antifungal activity against one yeast i.e. Aspergillus niger" should read: "antifungal activity against one fungus i.e. Aspergillus niger". The authors would like to confirm all antifungal activity has been screened against fungi not yeast.

6.
Drug Res (Stuttg) ; 68(2): 72-79, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28910831

RESUMO

The present study describes a multicomponent synthesis of molecular hybrid containing pyrazole, thiazole moiety using hydrazone as a linker, which have been synthesized by condensation of 1-phenyl-3-(aryl)-1H-pyrazole-4-carbaldehydes 1A-B: , thiosemicarbazide and α-bromoketones 2A-C: .The target hybrid compounds, 1-((1-phenyl-3-aryl-1H-pyrazole-4-yl)methylene)-2-(4-arylthiazole-2-yl)hydrazine 3A-F: are characterized by 1H-NMR, 13C NMR, FT-IR and mass. Apoptosis inducing ability and cytotoxic nature of all the hybrid compounds having thiazole, pyrazole and hydrazone were assessed by using biological assays viz morphological, fluorescence and tunel assays on granulosa cells of ovarian antral follicles of goat (Capra hircus) in vitro. Apoptosis was recognized and quantified using differential staining of ethidium bromide and acridine orange where apoptotic cells exhibited red fluorescence and live normal cells with intact cell membrane and normal nucleus displayed bright green fluorescence. Among the tested compounds, compound 3E: and 3B: showed the maximum potency to induce apoptosis with percentage of apoptosis 25.61±2.95and 23.45±1.46 respectively followed by 3F: (20.95±0.40) and 3D: (20.44±1.60) in comparison with control (5.14±0.44).


Assuntos
Apoptose/efeitos dos fármacos , Hidrazonas/síntese química , Hidrazonas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Células Cultivadas , Feminino , Cabras , Folículo Ovariano/efeitos dos fármacos , Relação Estrutura-Atividade
7.
Drug Res (Stuttg) ; 68(4): 189-195, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28992659

RESUMO

Monte Carlo method based QSAR studies for inhibitors of Mer kinase, a potential novel target for cancer treatment, has been carried out using balance of correlation technique. The data was divided into three random and dissimilar splits and hybrid optimal descriptors derived from SMILES and hydrogen filled graphs based notations were used for construction of QSAR models. The generated models have good fitting ability, robustness, generalizability and internal predictive ability. The external predictive ability has been tested using multiple criteria and described models exhibited good performance in all of these tests. The values of R2, Q2, R2test, Q2test, R2m and ∆R2m for the best model are 0.9502, 0.9388, 0.9469, 0.9083, 0.7534 and 0.0894 respectively. Also, the structural characteristics responsible for enhancement and reduction of activity have been extracted. Further, the agreement with the OECD rules for QSAR model has been discussed.


Assuntos
Preparações Farmacêuticas/química , Inibidores de Proteínas Quinases/química , c-Mer Tirosina Quinase/antagonistas & inibidores , Humanos , Método de Monte Carlo , Organização para a Cooperação e Desenvolvimento Econômico , Relação Quantitativa Estrutura-Atividade
8.
Chem Cent J ; 11(1): 115, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29138944

RESUMO

BACKGROUND: Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively. RESULTS: The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a-g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one yeast i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs. CONCLUSIONS: In vitro antiplasmodial IC50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.

9.
Sci Rep ; 7(1): 7906, 2017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801589

RESUMO

Accumulating evidence suggests that GDF15 is a biomarker for ageing and morbidity of many somatic disorders such as cancer and inflammatory disorders. Recently, elevated serum GDF15 level was proposed as a marker for mood disorder. However, psychosis severity was not investigated in relation to plasma GDF15 levels. In the present study we measured GDF15 levels in plasma of 120 psychosis patients compared to 120 age and gender matched healthy controls. Within the patient cohort GDF15 levels were evaluated for association with age, gender, lifestyle factors, C-reactive protein levels, psychosis severity and metabolic disorder. Psychosis patients had elevated GDF15 levels compared to controls (medianPsychosis = 744 ng/mL, mediancontrols = 516 ng/mL, p < 0.001). Within the psychosis cohort, GDF15 levels, when corrected for age, metabolic health and lifestyle factors, were negatively correlated with psychosis severity (ß = -0.218, p = 0.012). While GDF15 levels were elevated in patients versus healthy controls, the negative correlation between psychosis severity and GDF15 suggests a loss of anti-inflammatory GDF15 mediated functionality in severe psychosis. Study replication in larger cohorts will be necessary to assess the potential of GDF15 as a prognostic biomarker in psychosis.

10.
Photochem Photobiol Sci ; 16(5): 672-682, 2017 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-28267158

RESUMO

Photo-reorganization of 3-alkoxy-6-chloro-2-(benzo[b]thiophen-2-yl)-4H-chromen-4-ones in methanol with Pyrex filtered UV-light from a medium pressure 125 W Hg-vapor lamp led to the formation of angular pentacyclic compounds (dihydro and aromatic products) along with some rearranged chromenones where the product(s) distribution depended upon the structure of 3-alkoxy groups (methoxy, ethoxy, allyloxy and benzyloxy). The phenyl moiety in the 3-benzyloxy group had a profound effect on the dihydro product(s) formation as the latter was in high yield when the alkoxy group was benzyloxy followed by allyloxy, ethoxy and methoxy groups. The present photochemical study represents a general method for the synthesis of some angular pentacyclic - benzothiophene fused xanthenone derivatives in a single step without using any specific and toxic reagent. The structures of the new organic scaffolds obtained were established by their spectral data (UV, IR and NMR).

11.
Medchemcomm ; 8(7): 1468-1476, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108858

RESUMO

Postprandial hyperglycemia can be controlled by delaying the absorption of glucose resulting from carbohydrate digestion. α-Amylase is the initiator of the hydrolysis of polysaccharides, and therefore developing α-amylase inhibitors can lead to development of new treatments for metabolic disorders like diabetes mellitus. In the present work, we set out to rationally develop α-amylase inhibitors based on the thiazolidine-4-one scaffold. The structures of all these newly synthesized hybrids were confirmed by spectroscopic analysis (IR, 1H-NMR, MS). The appearance of two sets of signals for some protons in 1H NMR revealed the existence of a mixture of 2E,5Z (37.1-42.0%) and 2Z,5Z isomers (58.4-62.8%), which was further supported by DFT studies. All the newly synthesized compounds have potential inhibitory properties as revealed through in vitro α-amylase inhibition activity. Compound 5a at 100 µg mL-1 concentration showed a remarkable inhibition of 90.04%. In vitro α-amylase inhibition was further supported by docking studies of compound 5a against the active site of human pancreatic α-amylase (PDB ID: ; 2QV4). The docking studies revealed that the bonding interactions found between 5a and human pancreatic α-amylase are similar to those responsible for α-amylase inhibition by acarbose.

12.
J Allergy Clin Immunol ; 135(4): 1031-43.e6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25240785

RESUMO

BACKGROUND: Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-derived mediators into the circulation. OBJECTIVES AND METHODS: We report here that a plasma protease cascade, the factor XII-driven contact system, critically contributes to the pathogenesis of anaphylaxis in both murine models and human subjects. RESULTS: Deficiency in or pharmacologic inhibition of factor XII, plasma kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human factor XII restored susceptibility for allergen/IgE-mediated hypotension. Activated mast cells systemically released heparin, which provided a negatively charged surface for factor XII autoactivation. Activated factor XII generates plasma kallikrein, which proteolyzes kininogen, leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of factor XII, plasma kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal conditions or in healthy control subjects. The severity of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the intensity of contact system activation, and bradykinin formation. CONCLUSIONS: In summary, the data collectively show a role of the contact system in patients with anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.


Assuntos
Anafilaxia/imunologia , Anafilaxia/metabolismo , Fator XII/metabolismo , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Mastócitos/imunologia , Adulto , Idoso , Anafilaxia/complicações , Anafilaxia/genética , Animais , Biomarcadores , Bradicinina/metabolismo , Modelos Animais de Doenças , Fator XII/antagonistas & inibidores , Fator XII/genética , Feminino , Humanos , Hipersensibilidade/complicações , Hipersensibilidade/genética , Hipotensão/etiologia , Cininogênios/metabolismo , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Receptor B2 da Bradicinina/genética , Receptor B2 da Bradicinina/metabolismo , Transdução de Sinais , Fatores de Tempo , Adulto Jovem
13.
EXCLI J ; 12: 1030-42, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-27298613

RESUMO

A series of 3-aryl-1-phenyl-1H-pyrazole derivatives was synthesized in good yield and assayed in vitro as inhibitors of the mice acetylcholinesterase (AChE) and two goat liver monoamine oxidase (MAO) isoforms, MAO-A and MAO-B. Most of the compounds demonstrated a good AChE and selective MAO-B inhibitory activities in the nanomolar or low micromolar range. N-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-yl) methylene) benzenamine (3e, pIC50 = 4.2) and N-((4-fluorophenyl)-1-phenyl-1H-pyrazole-4-yl) methylene) methanamine (3f, pIC50 = 3.47) were the most potent AChE and highly selective MAO-B inhibitors respectively. Structure activity relationships showed that chloro derivatives were more effective AChE inhibitors as compared to fluoro derivatives while reverse trend was observed in MAO-B inhibitory activity. With the aid of modeling studies, potential binding orientations as well as interactions of the compounds in the AChE and MAO-B active sites were examined.

14.
Ultrason Sonochem ; 19(4): 729-35, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22296993

RESUMO

This project was undertaken to demonstrate the potential of iodobenzene diacetate for the oxidative aromatization of Hantzch-1,4-dihydropyridines under ultrasonic irradiation. All reactions were carried out under ultrasonic irradiation and results were compared with traditional method. Sonochemical switching was observed in case of oxidative aromatization of 4-n-alkyl substituted 1,4-DHP. Without sonication, dealkylation occurred in case of n-alkyl substituted 1,4-DHP (ionic mechanism) but under ultrasonic irradiation, n-alkyl group was not expelled (radical mechanism). However, secondary alkyl (isopropyl) and benzyl group were expelled under both conditions.


Assuntos
Acetatos/química , Iodobenzenos/química , Piridinas/síntese química , Sonicação , Catálise , Estrutura Molecular , Oxirredução , Piridinas/química
15.
Acta Pol Pharm ; 68(2): 191-204, 2011 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21485292

RESUMO

Various derivatives of decanoic acid (CD) have been synthesized and evaluated against Gram positive B. subtilis, S. aureus and Gram negative E. coli bacteria as well a sagainst fungi C. albicans and A. niger. Quantitative structure activity relationship (QSAR) models for antimicrobial activities were developed using multiple linear regression and cross validated by leave one out (LOO) approach. QSAR studies indicated that activity against Gram positive bacteria was governed by lipophilicity of the compounds while topologicalsteric nature of the molecule was deciding factor for antifungal activity. Further, in silico ADMET studies showed that compounds CD12, 19, 20 and 23 could be explored further for other activities.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Ácidos Decanoicos/síntese química , Ácidos Decanoicos/farmacologia , Anti-Infecciosos/metabolismo , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/crescimento & desenvolvimento , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/crescimento & desenvolvimento , Disponibilidade Biológica , Células CACO-2 , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Ácidos Decanoicos/metabolismo , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Humanos , Absorção Intestinal , Modelos Lineares , Testes de Sensibilidade Microbiana , Modelos Biológicos , Estrutura Molecular , Permeabilidade , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
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