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1.
J Fluoresc ; 33(1): 311-326, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36414920

RESUMO

From the last few years mode of interactions between drugs and DNA is an attractive research area as it bridges chemistry, molecular biology and medicinal science. Interactions between small heterocyclic molecules and human DNA is a noteworthy feature in pharmacology for investigation of drugs mechanism and designing of more effective and target specific drugs with fewer side effects. The present research work focuses on the theoretical investigations of 3-benzoyl-4-hydroxy-2-methyl-2H-1, 2-benzothiazine (SASA) by using Gaussian (16 W) software to predict optimized geometry, HOMO-LUMO gap, bond length, bond angle, dihedral angle, electronic and vibrational spectra. Possible reaction site observed in SASA was C7, C9 and C18 as these atoms show maximum charge density. Later the interactions of SASA with human DNA was explored spectroscopic investigations and viscometric investigations at physiological buffers of pH of 4.7 (stomach pH) and 7.4 (blood pH) respectively. Maximum absorbance between SASA-DNA complex was observed in buffer solution of pH 3.4 at wavelength of 370 nm, whereas at 7.4 has maximim absorbance between. Spectroscopic results reflects the bathochromic and hyperchromic shift succeeding the addition of human DNA. During viscosity measurement, intercalation and electrostatic mode of interaction were detected at low and high concentration of drug in solution respectively. Increase in the value of rate constant was observed with the increase in concentration of drug. Larger values of rate constant were observed at pH 7.4 in comparison to pH 3.5. Rate constant, thermodynamic parameters and viscometric analysis prefers the intake of SASA via blood.


Assuntos
Teoria Quântica , Análise Espectral Raman , Humanos , Modelos Moleculares , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , DNA , Espectrofotometria Ultravioleta
2.
Mol Divers ; 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37095354

RESUMO

Heterocyclic compounds are attractive candidates because of their vast applications in natural and physical sciences. Thienothiophene (TT) is an annulated ring of two thiophene rings with a stable and electron-rich structure. Thienothiophenes (TTs) fully represent the planar system, which can drastically alter or improve the fundamental properties of organic, π-conjugated materials when included into a molecular architecture. These molecules possessed many applications including, pharmaceutical as well as optoelectronic properties. Different isomeric forms of thienothiophene showed various applications such as antiviral, antitumor, antiglaucoma, antimicrobial, and as semiconductors, solar cells, organic field effect transistors, electroluminiscents etc. A number of methodologies were adopted to synthesize thienothiophene derivatives. In this review, we have addressed different synthetic strategies of various isomeric forms of thienothiophene that have been reported during last seven years, i.e., 2016-2022.

3.
J Integr Neurosci ; 22(5): 114, 2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37735131

RESUMO

BACKGROUND: Essential tremor (ET) is a common slowly-progressive neurologic disorder. It is predominantly characterized by kinetic tremors involving bilateral upper limbs. Although ET shares motor similarities with Parkinson disease (PD), there is no known relationship between ET and PD. METHODS: We studied white matter differences between 17 ET and 68 PD patients using standard diffusion tensor imaging and fixel-based analysis (FBA). Diffusion magnetic resonance imaging data were acquired from two scanners (General Electric (GE) and Philips) with different numbers of diffusion directions. Fractional anisotropy maps were generated by the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL), and FBA was performed using MRtrix3 to obtain fiber density, fiber bundle, and fiber density bundle cross-section. RESULTS: Compared with PD, significantly lower values of fiber density, fiber bundle, and fiber density bundle cross-section were found in the corpus callosum and left tapetum of the ET group. Additionally, significantly lower functional anisotropy values were found in the ET compared to the PD group, principally in the corpus callosum, corona radiata, and cingulum. In conclusion, differences in white matter integrity between ET and PD were observed by both FBA-based metrics and diffusion tensor imaging. CONCLUSIONS: Advanced diffusion-based metrics may provide a better understanding of the white matter microstructural characteristics in disparate motor-associated diseases with different underlying phenotypes, such as ET and PD.


Assuntos
Imagem de Tensor de Difusão , Tremor Essencial , Doença de Parkinson , Substância Branca , Humanos , Biomarcadores , Imagem de Difusão por Ressonância Magnética , Tremor Essencial/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
4.
Molecules ; 28(12)2023 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-37375415

RESUMO

The ongoing COVID-19 pandemic has resulted in a global panic because of its continual evolution and recurring spikes. This serious malignancy is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the outbreak, millions of people have been affected from December 2019 till now, which has led to a great surge in finding treatments. Despite trying to handle the pandemic with the repurposing of some drugs, such as chloroquine, hydroxychloroquine, remdesivir, lopinavir, ivermectin, etc., against COVID-19, the SARS-CoV-2 virus continues its out-of-control spread. There is a dire need to identify a new regimen of natural products to combat the deadly viral disease. This article deals with the literature reports to date of natural products showing inhibitory activity towards SARS-CoV-2 through different approaches, such as in vivo, in vitro, and in silico studies. Natural compounds targeting the proteins of SARS-CoV-2-the main protease (Mpro), papain-like protease (PLpro), spike proteins, RNA-dependent RNA polymerase (RdRp), endoribonuclease, exoribonuclease, helicase, nucleocapsid, methyltransferase, adeno diphosphate (ADP) phosphatase, other nonstructural proteins, and envelope proteins-were extracted mainly from plants, and some were isolated from bacteria, algae, fungi, and a few marine organisms.


Assuntos
Produtos Biológicos , COVID-19 , Humanos , SARS-CoV-2/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/química , Pandemias , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Simulação de Acoplamento Molecular
5.
Molecules ; 27(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36144750

RESUMO

The α-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. α-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its α-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better α-glucosidase inhibitions compared to the standard drug (acarbose IC50 = 58.8 ± 0.012 µM) with IC50 values of 15 ± 0.030, 19 ± 0.060, 25 ± 0.106, 21 ± 0.07 and 26 ± 0.035 µM, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand-receptor interactions.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores de Glicosídeo Hidrolases , Acarbose , Glicemia , Cloretos , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas , Sais/farmacologia , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
6.
Molecules ; 26(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065194

RESUMO

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 µM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.


Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Acetamidas/química , Acetamidas/uso terapêutico , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiazinas/síntese química
7.
Pak J Pharm Sci ; 34(5(Supplementary)): 1951-1955, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34836865

RESUMO

Diabetes mellitus (DM) is a metabolic disorder characterized by frequent urination, hunger and high blood sugar level. α-glucosidase inhibitors are considered as a frontline treatment for the DM. This research article deals with the identification of benzothiazine derivatives as α-glucosidase inhibitors through in-silico techniques and then the confirmation through in-vitro analysis. Molecular docking studies were carried out to find out the binding interactions of targeted molecules with receptor molecule i.e., α-glucosidase enzyme. The synthetic compounds 1 (a-n), 2 (a-d) and 3 (a-b) were evaluated for in-vitro alpha glucosidase inhibitory activities that resulted in the discovery of various potent molecules. Majority of the compounds (1c, 1f, 1g, 1k-n, 2a-d and 3a-b) exhibited good inhibitory activity against α-glucosidase. Compounds 1c, 1g, 1k and 1m appeared as the potent active compounds with the IC50 values 17.44, 27.64, 24.43, 42.59 and 16.90 µM respectively. Compounds 1c & 2c were found almost 3-folds more active than the standard acarbose. The study may lead to discover potent drug candidates with less complication for the treatment of the type II diabetes mellitus.


Assuntos
Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Tiazinas/síntese química , Tiazinas/farmacologia , Simulação por Computador , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
8.
J Pak Med Assoc ; 70(4): 583-590, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32296199

RESUMO

OBJECTIVES: To examine whether Ephrin type A receptor 2 gene polymorphisms are associated with susceptibility to age-related cataract. METHODS: The case-control study was conducted from January to May 2014 in Multan, Pakistan, and comprised patients of age-related cataract enrolled from Nishtar Hospital, Multan, and age-matched healthy controls without any type of cataract from the local population. A questionnaire was used to gather clinical and epidemiological data. Deoxyribonucleic acid was extracted from blood samples, and analysis of rs11260867, rs3568293 and rs7543472 single nucleotide polymorphisms was performed by using tetra amplification-refractory mutation system polymerase chain reaction protocol. Data was analysed using SPSS 17. RESULTS: Of the 230 subjects, 129(%) were patients and 101(%) were controls. Among the three polymorphisms analysed, rs7543472 was associated with age-related cataract. Among the epidemiological and clinical factors, age, diabetes, blood pressure, smoking, radiation exposure, steroids usage and use of tranquilisers were associated with age-related cataract (p<0.05 each). CONCLUSIONS: Polymorphism rs7543472 was found to be associated with age-related cataract.


Assuntos
Catarata , Efrina-A2/genética , Idade de Início , Idoso , Estudos de Casos e Controles , Catarata/diagnóstico , Catarata/epidemiologia , Catarata/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único , Receptor EphA2
9.
Pak J Pharm Sci ; 33(2(Supplementary)): 847-854, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32863261

RESUMO

Pyrazoline and benzimidazoles derivatives have been widely studied due to their potential applications in the medicinal field. In this research project, we have hybridized these two heterocyclic systems in the same molecule. A new series of compounds, 2-((3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)methyl)-1H-benzo[d]imidazole (5a-i) were synthesized through a multistep reaction. In the first step, chalcones 3a-i were prepared by coupling of various acetophenones and benzaldehydes under alkaline conditions. These chalcones were cyclized with hydrazine hydrate to form a series of pyrazolines which were finally coupled with 2-chloromethyl-1H-benzimidazole to get a new series of titled hybrid molecules. The structures of these compounds were elucidated by spectral (1H NMR and 13C NMR) analysis. The anti-diabetic potential of these compounds was studied by screening them for their α-glucosidase inhibition activity. The SAR was established through molecular docking analysis. Compound 5d appeared as effective inhibitor with IC50 = 50.06µM as compared to reference drug (acarbose) having IC50 = 58.8µM.


Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Benzaldeídos/síntese química , Benzaldeídos/farmacologia , Chalconas/síntese química , Chalconas/farmacologia , Hidrazinas/síntese química , Hidrazinas/farmacologia , Simulação de Acoplamento Molecular/métodos , Relação Estrutura-Atividade
10.
Pak J Pharm Sci ; 33(2(Supplementary)): 855-860, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32863262

RESUMO

The drug resistance phenomenon in microbes is resulting in the ineffectiveness of available drugs to treat the infections. Thus, there is a continued need to discover new molecules to combat the drug resistance phenomenon. Norfloxacin is a fluoroquinolone antibiotic that is used for the treatment of urinary tract infections. In this research work, norfloxacin is structurally modified by hybridizing with a range of substituted acetohydrazidic moieties through a multistep reaction. The first step involves the coupling of norfloxacin 1 with methyl chloroacetate followed by the treatment with hydrazine hydrate to result in corresponding acetohydrazide 3. A range of substituted benzaldehydes were reacted with the acetohydrazide to form the targeted series of norfloxacin derivatives 4a-i. The final compounds were screened for antimicrobial activity. Among the tested compounds, 4c, 4d, 4e and 4f displayed better antifungal activity against F.avenaceum, while compound 4c and 4e were active against F. bubigeum.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Hidrazinas/síntese química , Hidrazinas/farmacologia , Norfloxacino/síntese química , Norfloxacino/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Benzaldeídos/química , Fungos/efeitos dos fármacos , Hidrazinas/química , Relação Estrutura-Atividade
11.
Pak J Pharm Sci ; 32(6(Supplementary)): 2795-2800, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32024616

RESUMO

Four series of pyrazolobenzothiazine derivatives were evaluated for their anticancer activity against six different cancer cell lines i.e., KB (human oral carcinoma cells), MCF-7(human breast carcinoma cells), A549 (human alveolar adenocarcinoma cells), Hep-G2 (liver carcinoma cells), SGC-7901(human gastric carcinoma cells) and S1 (human colon carcinoma cells) using MTT assay. Among eighteen compounds tested, six compounds i.e., 1a, 1b, 1d, 4a, 4d and 4e were more active than 5-florouracil against human oral carcinoma cells (KB). Moreover, compounds 2b and 2c showed activity comparable to 5-FU against KB cell line. In addition, eight compounds were non-toxic to human PBM cells and thus exhibit selective anticancer activity.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células Hep G2 , Humanos , Células KB , Células MCF-7 , Relação Estrutura-Atividade
12.
Pak J Pharm Sci ; 32(6(Supplementary)): 2829-2834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32024621

RESUMO

Diabetes Mellitus is a chronic disease in which the infected cells do not have the ability to produce sufficient amount of insulin that resulted in the abnormality of carbohydrates metabolism and an increase in blood glucose level. Long time exposure to Diabetes Mellitus resulted in failure or dysfunction of different organs like kidneys, nerves, heart, eyes, etc. A common practice to cure diabetes is the use of α-glucosidase inhibitors which help in lowering the blood glucose level. We presented 1,2-benzothiazine 1,1-dioxide derivatives as novel and more potent α-glucosidase inhibitors via their in vitro and in silico screenings. Excellent enzyme inhibitions were observed for compounds 2, 8, 10 and 12 having IC50 values of 6.91, 14.0, 4.2, 5.9 and 29.2µ respectively which were found better than the reference acarbose (IC50=38.31µM). Molecular docking studies suggested high binding energies and good binding interactions of these compounds with the active site residues of the receptor protein. A good agreement was found between the results of both modes of evaluation. Moreover, the envisioned candidates have a good potential to treat diabetes.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Hidrazinas/farmacologia , Hipoglicemiantes/farmacologia , Tiazinas/farmacologia , alfa-Glucosidases/metabolismo , Acarbose/farmacologia , Humanos , Cinética , Simulação de Acoplamento Molecular/métodos , Relação Estrutura-Atividade
13.
Bioorg Chem ; 80: 498-510, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996111

RESUMO

In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues.


Assuntos
Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Tiazinas/química , Tiazinas/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Óxidos/síntese química , Óxidos/química , Óxidos/farmacologia , Relação Estrutura-Atividade , Tiazinas/síntese química
14.
Int Ophthalmol ; 38(3): 1135-1146, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28560653

RESUMO

PURPOSE: Age-related cataract (ARC) is a multifactorial disease and different risk factors, including genetic and environmental, are responsible for the development of its various types. The aim of this study was to find out a correlation, if any, between ARC and the single nucleotide polymorphisms (SNPs) in DNA repair genes XRCC1 (X-ray repair cross-complementary-1) [Arg194Trp (rs1799782)] and XPD (xerodermapigmentosa complementation group D) [Lys751Gln (rs13,181]. METHOD: The genotype at these two SNPs was analyzed in 260 subjects (125 control and 135 patients) from Southern Punjab population (Pakistan) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Genotype at both analyzed codons was correlated either individually or in various combinations with the studied epidemiological factors known to be associated with ARC. RESULTS: Our results indicated that both SNPs Arg194Trp in XRCC1 (P = 0.967) and Lys751Gln in XPD (P = 0.995) were not associated with ARC whether they were analyzed individually or in combined form (P > 0.05). Analysis of epidemiological factors revealed that age (P < 0.001), cast of subjects (P = 0.001), diabetes (P < 0.001), hypertension (P = 0.001), smoking habit (P = 0.01), drug abuse (P < 0.05), steroid use (P = 0.001) and body weight (P < 0.001) can influence the incidence of ARC in enrolled subjects. After applying Binary logistic regression it was found that the weight (P < 0.01), family history (P = 0.05), drug abuse (P = 0.05), smoking (P < 0.05) and steroid use (P < 0.05) has a significant association with the phenotype of the subjects. All epidemiological factors were also studied in association with various genotypic combinations of both SNPS, diabetes was the only factor that had a significant association (P < 0.001) association with ARC. Hypertension (P = 0.01), body weight (P < 0.05) and cast (P < 0.001) were found associated with ARC when epidemiological factors were individually correlated with ARC. Result of the two proportion test indicated that gender had no influence on the incidence of disease. CONCLUSION: It is concluded that studied SNPs in XRCC1 and XPD have no association with the incidence of age related cataract in the analyzed group of subjects.


Assuntos
Catarata/genética , DNA/genética , Medição de Risco/métodos , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Catarata/epidemiologia , Catarata/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
15.
Pak J Pharm Sci ; 29(2): 367-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27087086

RESUMO

A collection of forty halophilic actinomycetes isolated from water and mud samples of the saline lake at Kalar Kahar, salt range, Pakistan, was screened to investigate their antimicrobial potential against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens. The isolates exhibited significant tolerance to alkaline conditions and grew well at pH 9-11. The taxonomic status of the isolated strains was determined by morphological, biochemical and physiological characterization and by 16s rRNA gene sequencing. The results revealed that majority of the isolates (90%) belong to the genus Streptomyces. Most of the isolates exhibited remarkable antimicrobial activity up to 20mm zone of inhibition against MDR ventilator associated pneumonia causing bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Escherichia coli, Enterobacter and Acinetobacter spp. Additionally the isolates showed moderate to high cytotoxicity in the range of 40 to 80% larval mortality against Artemia salina in a micro well cytotoxicity assay. The chemical screening or the so called metabolic fingerprinting of the methanolic extracts of each isolate, by thin layer chromatography (TLC) using various staining reagents and by high performance liquid chromatography (HPLC-UV), indicated an impressive diversity of the compounds produced by these strains. The study reveals that these halophilic actinomycetes are a promising source of bioactive compounds. The preparative scale fermentation, isolation, purification and structure elucidation of the compounds produced by them may yield novel antimicrobial or chemotherapeutic agents.


Assuntos
Actinobacteria/metabolismo , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Actinobacteria/classificação , Actinobacteria/genética , Actinobacteria/crescimento & desenvolvimento , Actinobacteria/isolamento & purificação , Antibacterianos/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , DNA Bacteriano/genética , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Humanos , Lagos/microbiologia , Metabolômica/métodos , Paquistão , Filogenia , Pneumonia Associada à Ventilação Mecânica/microbiologia , RNA Ribossômico 16S/genética , Ribotipagem , Águas Salinas , Microbiologia da Água
16.
Bioorg Med Chem Lett ; 25(6): 1348-51, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25701249

RESUMO

Two series of fifteen N-substituted benzyl/phenyl-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl)acetamides were screened for anti-HIV-1 activity and cytotoxicity. The compounds 6a, 6d, 6e, 6g and 6i from the series 6a-i of benzylamides and 7a, 7b, 7c, 7d and 7e from the series 7a-f of anilides were identified as effective anti-HIV-1 agents with EC50 values <20µM. Among these compounds that displayed anti-HIV-1 activity, 6a, 6e, 6g and 6i showed no toxicity in human PBM, CEM and Vero cells, with the exception of 6a which displayed toxicity in Vero cells. Molecular docking of these compounds provided insight into the molecular mechanism and it was found that 6e, 6g and 6i bound deeply in the NNRTI binding pocket of the HIV-1 reverse transcriptase, using RT-bound nevirapine X-ray data and molecular docking for validation, showing the potential of these new structures as inhibitors of this viral enzyme.


Assuntos
Acetamidas/química , Antivirais/química , Inibidores da Transcriptase Reversa/química , Animais , Antivirais/síntese química , Antivirais/toxicidade , Sítios de Ligação , Domínio Catalítico , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Simulação de Acoplamento Molecular , Nevirapina/química , Nevirapina/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/toxicidade , Células Vero
17.
Med Chem Res ; 24(10): 3671-3680, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34316244

RESUMO

A series of fifteen new 2-[3-(3-chlorophenyl)-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(2H)-yl]-N'-arylmethyleneacetohydrazides (5a-o) were synthesized and screened for their anti-HIV-1 and cytotoxicity activity. Out of fifteen pyrazolobenzothiazine-based hydrazones, thirteen were found to be active inhibitors of HIV with EC50 values <20 µM. Moreover, the cytotoxicity results showed that most of the compounds were toxic to PBM, CEM and Vero cell lines. This information could be used for structural modifications to acquire good candidates of HIV drugs.

18.
Parkinsonism Relat Disord ; 123: 106065, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38418318

RESUMO

There is no consensus driven definition of "advanced" Parkinson's disease (APD) currently. APD has been described in terms of emergence of specific clinical features and clinical milestones of the disease e.g., motor fluctuations, time to increasing falls, emergence of cognitive decline, etc. The pathological burden of disease has been used to characterize various stages of the disease. Imaging markers have been associated with various motor and nonmotor symptoms of advancing disease. In this review, we present an overview of clinical, pathologic, and imaging markers of APD. We also propose a model of disease definition involving longitudinal assessments of these markers as well as quality of life metrics to better understand and predict disease progression in those with Parkinson's disease.


Assuntos
Progressão da Doença , Doença de Parkinson , Doença de Parkinson/fisiopatologia , Doença de Parkinson/diagnóstico por imagem , Humanos
19.
Drug Des Devel Ther ; 18: 1547-1571, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38737333

RESUMO

The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Compostos Heterocíclicos , SARS-CoV-2 , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19
20.
Cureus ; 16(3): e56282, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38623137

RESUMO

Background and objective Alopecia areata (AA) is a reiterative and nonscarring type of hair loss that can affect any hairy area of the body, particularly the scalp. It manifests as patchy or confluent hair loss with variations in demographics and ethnicity. There are numerous treatment options available, including topical and systemic steroids, topical minoxidil, dithranol, tacrolimus, psoralen and ultraviolet therapy (PUVA), contact immunotherapy, and oral immunosuppressive drugs. However, no previous contrast for efficacy is present between the topical betamethasone versus topical minoxidil alone in our population. This study aims to compare the efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA. Methodology A nonrandomized controlled study was conducted at the Department of Dermatology, Jinnah Hospital Lahore, incorporating the data of patients between July 26, 2016, and January 26, 2017, after obtaining institutional ethical approval. One hundred patients with alopecia, either on the scalp or any other hairy part, from both genders, aged between 18 and 50 years, were included in the study. Two groups were created, and patients were assigned to these groups based on the clinician's choice. Group A patients were administered betamethasone dipropionate (0.05%) lotion twice daily on affected areas for 12 weeks. Group B patients were administered minoxidil (5%) solution twice daily on affected areas for 12 weeks. A four-week follow-up plan was followed. A five-point scale score system was used for alopecia grading. After 12 weeks, the hair regrowth score (RGS) was used to compare the efficacy of treatment between the two groups. Results A total of 100 patients with grades S1 to S3 AA of less than three months duration were enrolled. Two groups were created, with 50 patients in each group. The mean age in Group A was 29.08 ± 6.51 years, while in Group B, it was 29.38 ± 6.62 years. In Group A, there were 76% males and 24% females, while in Group B, there were 74% males and 26% females. Comparison of efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA demonstrated a greater efficacy of 74% (Grade 3 and Grade 4 responses) in Group A, while in Group B, only 42% of patients showed efficacy. A statistically significant difference was found, with a P-value of 0.001. No serious side effects were noted. Conclusions Our study concluded that topical betamethasone dipropionate (0.05%) lotion has statistically significantly higher efficacy compared to topical minoxidil (5%) solution in patients with AA.

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