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1.
J Ayub Med Coll Abbottabad ; 32(3): 389-394, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32829557

RESUMO

BACKGROUND: Various methods for mandibular reconstruction have been demonstrated in literature from autogenous bone graft to free flaps and more recently tissue engineered materials. We share our experience of mandibular reconstruction with free fibular flap and evaluate its efficiency as a viable option for mandibular reconstruction. METHODS: It was a cross-sectional study, conducted at Plastic surgery department combined military hospital, Rawalpindi. Study was carried out over a period of two years from November 2016 to November 2018. The data of demography, mode of presentation, pattern of reconstruction and procedural complications of the patients who underwent free fibula flap for segmental mandibular loss, were collected and analysed. Patients with segmental loss of mandible ranging from 6 to 15 cm and those who could sustain surgery were included in the study, while the patients with metastatic malignancy and recurrent disease were excluded from the study. Each patient was called for first follow up after 2 weeks then subsequent follow up after 1 month. Descriptive statistics were done with the help of SPSS-20. RESULTS: A total of 57 patients with segmental mandibular loss treated with free fibula flap, fulfilling inclusion and exclusion criteria were included in this study. Thirtyeight patients were male while 19 were female with mean age 56±3 years. Cause of mandibular loss was malignancy in 52 (91.2%), trauma in 3 (5.2%), and ameloblastoma in 2 (3.5%) patients. Major complications like flap failure was seen in one (1.75%), bone exposure in 1 (1.75%) and recurrence was observed in 1 (1.75%) patient. Minor complications like hematoma, wound dehiscence and oro-cutaneous fistula were seen in 2, 1 and 3 patients respectively. CONCLUSIONS: Free fibular flap shows good functional results with a high degree of consistency, and acceptable complications rate, so it should be the first choice for mandibular reconstruction.

2.
Nat Genet ; 52(7): 680-691, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541925

RESUMO

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Afro-Americanos , Cromossomos Humanos X , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/genética , Europa (Continente) , Feminino , Estudos de Associação Genética , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Polimorfismo de Nucleotídeo Único , Medição de Risco
3.
Bioorg Chem ; 101: 103999, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32563966

RESUMO

In this study, we have discovered small druglike molecules as selective inhibitors of human tissue-nonspecific alkaline phosphatase (h-TNAP), an enzyme critical for the regulation of extracellular matrix calcification. The upregulation of h-TNAP is associated with various pathologies particularly the vascular calcification (VC). Selective inhibition of h-TNAP over h-NPP1 may serve as a useful therapeutic strategy against vascular calcification. A series of novel triazolyl pyrazole derivatives (10a-y) in which thiol bearing triazole moiety as the zinc binding functional group was introduced to a pyrazole based pharmacophore was synthesized and evaluated as potent and selective inhibitors of h-TNAP over h-NPP1. The biological screening against h-TNAP, h-IAP, h-NPP1 and h-NPP3 showed that many of the synthesized compounds are selective inhibitors of TNAP. Particularly, the compounds 10a-h, 10j, 10m-q, 10u, 10w and 10x displayed high potency and complete selectivity towards h-TNAP over h-NPP1. Compound 10q emerged as a highly potent inhibitor (IC50 = 0.16 µM or 160 nM) against h-TNAP with 127-fold increased inhibition compared to levamisole. On the other hand, compound 10e was found to be most selective inhibitor against the tested APs and NPPs (IC50 = 1.59 ± 0.36 µM). Binding sites architecture analysis, molecular-docking and molecular dynamics simulations (MDS), revealed the basis for h-TNAP and h-IAP ligand selectivity as well as selectivity towards h-TNAP over h-NPP1. These newly discovered inhibitors are believed to represent valuable lead structures to further streamline the generation of candidate compounds to target VC.

4.
Bioorg Chem ; 96: 103567, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32062063

RESUMO

Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC50 values of 13.9 µM and 15.1 µM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.

5.
Arch Pharm (Weinheim) ; 352(8): e1900061, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31338866

RESUMO

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.


Assuntos
Hidrocarbonetos Fluorados/farmacologia , Elastase Pancreática/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Serino Proteinase/farmacologia , Animais , Relação Dose-Resposta a Droga , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Ligantes , Modelos Moleculares , Estrutura Molecular , Pâncreas/enzimologia , Elastase Pancreática/metabolismo , Piperidinas/síntese química , Piperidinas/química , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade , Suínos
6.
Bioorg Chem ; 88: 102893, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30986550

RESUMO

With the aim to discover novel, efficient and selective inhibitors of human alkaline phosphatase and nucleotide pyrophosphatase enzymes, two new series of pyrazolyl pyrimidinetriones (PPTs) (6a-g) and thioxopyrimidinediones (PTPs) (6h-n) were synthesized in good chemical yields using Knoevenagel condensation reaction between pyrazole carbaldehydes (4a-g) and pharmacologically active N-alkylated pyrimidinetrione (5a) and thioxopyrimidinedione (5b). The inhibition potential of the synthesized hybrid compounds was evaluated against human alkaline phosphatase (h-TNAP and h-IAP) and ectonucleotidase (h-NPP1 and h-NPP3) enzymes. Most of the tested analogs were highly potent with a variable degree of inhibition depending on the functionalized hybrid structure. The detailed structure-activity relationship (SAR) of PPT and PTP derivatives suggested that the compound with unsubstituted phenyl ring from PPT series led to selective and potent inhibition (6a; IC50 = 0.33 ±â€¯0.02 µM) of h-TNAP, whereas compound 6c selectively inhibited h-IAP isozyme with IC50 value of 0.86 ±â€¯0.04 µM. Similarly, compounds 6b and 6h were identified as the lead scaffolds against h-NPP1 and h-NPP3, respectively. The probable binding modes for the most potent inhibitors were elucidated through molecular docking analysis. Structure-activity relationships, mechanism of action, cytotoxic effects and druglikeness properties are also discussed.


Assuntos
Barbitúricos/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Tionas/farmacologia , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/química , Fosfatase Alcalina/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Barbitúricos/síntese química , Barbitúricos/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/metabolismo , Humanos , Cinética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Ligação Proteica , Pirazóis/síntese química , Pirazóis/metabolismo , Pirofosfatases/antagonistas & inibidores , Pirofosfatases/química , Pirofosfatases/metabolismo , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/metabolismo
7.
Eur J Med Chem ; 168: 154-175, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30818176

RESUMO

A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293).


Assuntos
Aldeído Redutase/antagonistas & inibidores , Antioxidantes/farmacologia , Imidazóis/farmacologia , Insulina/metabolismo , Sorbitol/metabolismo , Compostos de Espiro/farmacologia , Aldeído Redutase/química , Aldeído Redutase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Células Cultivadas , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade
8.
Med Chem ; 15(8): 892-902, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747078

RESUMO

BACKGROUND: Cancer is a far-reaching and lethal but curable disease. Researchers have investigated numerous anticancer agents with only a few commercially available effective drugs which are very costly. OBJECTIVE: Herein, we report the synthesis , characterization and anti cancer assays of a series of novel dithiocarbamates derivatives. METHODS: All compounds were synthesized from different secondary amines and substituted benzyl chlorides in a single step. The structures of newly synthesized dithiocarbamate derivatives were confirmed by spectroscopic techniques (IR, NMR and HR-MS). RESULTS: The synthesized compounds showed a significant anti-proliferative effect in cancer cells (HeLa) with the maximum inhibitory activity of compound SHD-2 with an IC50 = 0.31 ± 0.09 µM. However, the same compound exhibited 19.2% inhibition towards Baby Hamster Kidney fibroblasts (BHK-21), normal cell lines. Moreover, quantification of cellular DNA by flow cytometry for the evaluation of pro-apoptotic activity in HeLa cells demonstrates that arrest in cell cycle along with apoptosis advance towards drug cytotoxicity. However, molecular docking studies of the potent compound suggested that it binds to the major groove of the DNA. CONCLUSION: The cytotoxic and pro-apoptotic potential of the potent inhibitor may be further investigated in the animal models to advance their anti-cancer prospective.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Simulação por Computador , Desenho de Fármacos , Tiocarbamatos/química , Tiocarbamatos/farmacologia , Animais , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , DNA/química , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Relação Estrutura-Atividade , Tiocarbamatos/metabolismo
9.
Med Chem ; 15(3): 298-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30324884

RESUMO

BACKGROUND: The over-expression of the carbonic anhydrases results in some specific carcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxic conditions and various investigations are being carried out to target the known hypoxic areas of the tumors to increase the sensitivity towards standard therapeutic treatment. OBJECTIVE: Herein, we have designed and synthesized some biologically important esters, hydrazides, thiocarbamates, 1,2,4-triazole-3-thiones and Schiff bases. The purpose of the research was to evaluate the derivative against carbonic anhydrase and to assess the toxicity of the same compounds. METHOD: The structures of all the compounds were characterized by FT-IR, mass spectrometry, elemental analysis, 1H and 13C NMR spectroscopy. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plots for inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined. Furthermore, to check the cytotoxicity, these derivatives were tested against human breast adenocarcinoma by MTT method. RESULTS: X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not have any π-π or C-H…π interactions. The experimental results were validated by molecular docking and dynamic simulations of the potent compounds in the active pocket of enzyme. Important binding interactions of potent compounds with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine the physicochemical properties. CONCLUSION: The proposed synthetic approach provides a suitable platform for the generation of a new library of compounds which could potentially be employed in the future testing and optimization of inhibitor potencies.


Assuntos
Benzoatos/química , Inibidores da Anidrase Carbônica/farmacologia , Flurbiprofeno/análogos & derivados , Ibuprofeno/análogos & derivados , Triazóis/química , Benzoatos/farmacologia , Cristalografia por Raios X , Flurbiprofeno/farmacologia , Ibuprofeno/farmacologia , Simulação de Acoplamento Molecular , Bases de Schiff/química , Análise Espectral/métodos , Relação Estrutura-Atividade
10.
Acta Crystallogr C Struct Chem ; 74(Pt 7): 816-829, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29973421

RESUMO

To explore the operational role of noncovalent interactions in supramolecular architectures with designed topologies, a series of solid-state structures of 2- and 4-formylphenyl 4-substituted benzenesulfonates was investigated. The compounds are 2-formylphenyl 4-methylbenzenesulfonate, C14H12O4S, 3a, 2-formylphenyl 4-chlorobenzenesulfonate, C13H9ClO4S, 3b, 2-formylphenyl 4-bromobenzenesulfonate, C13H9BrO4S, 3c, 4-formylphenyl 4-methylbenzenesulfonate, C14H12O4S, 4a, 4-formylphenyl 4-chlorobenzenesulfonate, 4b, C13H9ClO4S, and 4-formylphenyl 4-bromobenzenesulfonate, C13H9BrO4S, 4c. The title compounds were synthesized under basic conditions from salicylaldehyde/4-hydroxybenzaldehydes and various aryl sulfonyl chlorides. Remarkably, halogen-bonding interactions are found to be important to rationalize the solid-state crystal structures. In particular, the formation of O...X (X = Cl and Br) and type I X...X halogen-bonding interactions have been analyzed by means of density functional theory (DFT) calculations and characterized using Bader's theory of `atoms in molecules' and molecular electrostatic potential (MEP) surfaces, confirming the relevance and stabilizing nature of these interactions. They have been compared to antiparallel π-stacking interactions that are formed between the arylsulfonates.

11.
Mol Divers ; 22(4): 957-968, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29968121

RESUMO

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 µM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 µM and could be a promising antiproliferative agent.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Sulfonamidas/química , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Técnicas de Química Sintética , Humanos , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/toxicidade
12.
Chem Cent J ; 12(1): 25, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29516202

RESUMO

Apart from its numerous biological activities like antidiabetic, anti-inflammatory, antimicrobial, pyrazine moiety plays an important role in luminescent materials. Its role in luminescent materials is due to its highly electron deficient nature specially when it is in the centre along the mainstay of extended π-conjugated systems. Similarly, new liquid crystalline compounds are being made constantly where the central benzoaromatic moiety is being replaced with the heterocycles including pyrazine due to their more variable nature. Pyrazine derivatives can also be used in supramolecular assemblies due to their efficient hydrogen bonding, protonation and complexation properties. Keeping in view the enormous applications of pyrazine derivatives we planned to synthesize new extended iminobenzoates with pyrazine moieties at the terminal positions. The planned iminobenzoates with terminal pyrazine moieties were prepared following standard procedures. The pyrazine-2-carbohydrazide (1) and 5-methylpyrazine-2-carbohydrazide (2) were prepared by refluxing their methyl esters with hydrazine hydrate in methanol. The esters (3a-3f) were synthesized by reacting 4-hydroxybenzaldehyde with differently substituted acid halides in tetrahydrofuran in the presence of triethyl amine. The target compounds that is, iminobenzoates with the pyrazine moieties at terminal positions (4a-4l), were obtained in good to excellent yields by the reaction of the hydrazides with the esters at reflux. The synthesized compounds were fully characterized using different spectroanalytical techniques including FT-IR, NMR, Mass, elemental analysis and single crystal X-ray diffraction analysis. The paper describes the synthesis of novel iminobenzoates following easy methods while utilizing commercially available starting materials. The synthesized iminobenzoates may possibly be converted to compounds with luminescent and liquid crystalline properties after making suitable changes to the pyrazine moieties. Properly substituted pyrazines on both sides, capable of further suitable extensions, may result in compounds with such properties.

13.
Med Chem ; 14(1): 74-85, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28545383

RESUMO

BACKGROUND: Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. OBJECTIVES: To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. METHODS: In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a-j) and evaluated their in vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the druglikeness of the compounds. RESULTS: The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted both the isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 ±µM. CONCLUSION: The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders.


Assuntos
Ácidos Carboxílicos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/tratamento farmacológico , Quinolinas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Ácidos Carboxílicos/química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Quinolinas/química , Relação Estrutura-Atividade
14.
Bioorg Chem ; 75: 1-15, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28888096

RESUMO

In the present study, the pharmacophore integration methodology provided an efficient access to a new library of thioxothiazolidinone-sulfonate conjugates (8a-r) from easily available synthetic precursors. The approach was excellently high yielding with flexible structural sites for chemical modifications. The designed hybrid scaffolds were assessed for aldehyde/aldose reductase inhibition activities. The results for the in vitro bioassays were promising with the identification of compound 8e as the lead and selective candidate for ALR2 inhibition with an IC50 value of 0.468±0.003µMas compared to 3.1±0.2µM for the standard (sorbinil), whereas compound 8o demonstrated high inhibitory potency for both ALR2 and ALR1 enzymes. Molecular modeling analysis of the potent compounds provided further insight into the biological properties where detailed binding mode analysis revealed that the conjugates (8a-r) were found stabilized in the active site of the enzymes through the development of a number of interactions with catalytic residues.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Ácidos Sulfônicos/química , Tiazóis/química , Aldeído Redutase/isolamento & purificação , Aldeído Redutase/metabolismo , Animais , Sítios de Ligação , Domínio Catalítico , Bovinos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Cristalino/enzimologia , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/isolamento & purificação , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade
15.
Chem Biol Drug Des ; 89(2): 243-256, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28205403

RESUMO

Calixarenes, composed of phenolic units linked by methylene bridges at the 2,6-positions, represent a versatile class of macrocyclic compounds in supramolecular chemistry that can host small molecules or ions in their well-defined hydrophobic cavities. In recent years, it has been recognized that this class of compounds has the potential to serve as platform for the design of biological active compounds. Therefore, the calixarenes functionalized with different pharmacophoric groups have been synthesized as target structure by many researchers and were further evaluated for their biological activities. Owing to their promising biological activities such as antiviral, antibacterial, antifungal, and anticancer, the functionalized calixarenes are recently receiving increased attention from pharmaceutical/medicinal chemistry community. In this review, we summarize and discuss the synthetic approaches and the biological potential of functionalized calixarenes, mainly focusing on the selected recent studies for a comprehensive and target-oriented information, which could help in the design and synthesis of new therapeutic agents leading to the development of clinically viable drugs based on these macrocyles.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Fenóis/química , Relação Estrutura-Atividade
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 171: 432-438, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27572737

RESUMO

Cu2+ and Fe3+ complexes of three flavonoids (morin or mo, quercetin or quer and primuletin or prim) were synthesized with the objective of improving antioxidant capacities of flavonoids. The radical scavenging activities of pure flavonoids and their metal complexes were assayed to monitor their tendencies towards sequestering of radicals at physiological conditions. The scavenger potencies of metal-flavonoid complexes were significantly higher than those of the parent flavonoids. Further, influence of the solvent polarity on the radical capturing by flavonoids and their metal complexes was in favor for the polar solvent. Fe3+-prim displayed its radical scavenging ability via up gradation of CAT and SOD activities in in-vivo antioxidant assays.


Assuntos
Complexos de Coordenação/química , Cobre/química , Flavonoides/química , Depuradores de Radicais Livres/química , Ferro/química , Antioxidantes/química , Compostos de Bifenilo/química , Eletroquímica , Concentração Inibidora 50 , Modelos Moleculares , Picratos/química , Teoria Quântica , Solventes/química , Espectrofotometria Ultravioleta , Termodinâmica
17.
Pak J Pharm Sci ; 29(3): 811-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27166526

RESUMO

Pyrazine carbohydrazide based hydrazones were synthesized starting from 5-methylpyrazine-2-carboxylic acid. The acid was first converted to its methyl ester, which on further treatment with hydrazine hydrate transformed to carbohydrazide. The carbohydrazide was treated with differently substituted aromatic carbonyl compounds giving hydrazones. Characterization of the synthesized compounds was carried out using modern spectroscopic techniques and unambiguously confirmed through X-ray crystallographic studies of compound 3d. The purity of the compounds was verified using elemental analysis. The target molecules were evaluated for urease inhibition, antioxidant and antimicrobial activity.


Assuntos
Desenho de Fármacos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Urease/antagonistas & inibidores , Urease/metabolismo
18.
J Ayub Med Coll Abbottabad ; 27(2): 451-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26411138

RESUMO

BACKGROUND: Thoracodorsal artery perforator flap (TAP) is a feasible option to reconstruct defects in upper limb where only skin and subcutaneous tissue is required. METHODS: This case series was carried out at department of Plastic and Reconstructive Surgery Combined Military Hospital Rawalpindi. A total of 5 patients with upper limb defects were reconstructed with thoracodorsal artery musculocutaneous perforator flaps. Among them, 3 were pedicled and two free TAP flaps. All flaps except one pedicled flap were raised on a single perforator pedicle. Recipient sites were one axilla, two shoulder regions and two hands. The soft tissue defects in the patients had resulted from burns, trauma, wide local excision of synovial sarcoma and surgery for hidradenitis suppurativa. Preoperative hand held Doppler ultrasound was used to locate and mark the perforator. RESULTS: All flaps survived without significant complications. All flaps were hyperemic in the immediate postoperative period. We designed and raised all the five flaps on eccentrically placed perforators. All the raised perforators originated from the descending branch of the thoracodorsal artery. The donor sites were closed primarily with linear scars in all cases except one, in which partial closure was accomplished with split thickness skin grafting (STSG). CONCLUSION: The thoracodorsal artery perforator flap has great potential for reconstructing large, relatively shallow, defects of upper limb because of its suitable skin quality, texture and appropriate thickness, as well as hidden donor site, a reliable pedicle and sparing of muscle unit.


Assuntos
Artérias/cirurgia , Axila/irrigação sanguínea , Retalho Perfurante , Procedimentos Cirúrgicos Reconstrutivos/métodos , Extremidade Superior/irrigação sanguínea , Procedimentos Cirúrgicos Vasculares/métodos , Adulto , Feminino , Humanos , Masculino
19.
Eur J Med Chem ; 98: 127-38, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26005026

RESUMO

A series of 3-arylsulfonylspiroimidazolidine-2,4-diones (2a-g) and their corresponding rearranged products, 1-arylsulfonylspiroimidazolidine-2,4-diones (3a-g) were synthesized and evaluated for antidiabetic and aldose reductase inhibition activity. Three of the compounds (2b, 2c and 3c) were found more potent in-vivo hypoglycemic agents than the commercial drug glibenclamide. The free energy of binding (ΔG) values showed that the compounds are active against aldose reductase and aldehyde reductase enzymes, which was also estimated using molecular mechanics Poisson-Boltzmann surface area method. Of the tested compounds, 2b was found to be the most potent in-vitro selective inhibitor of ALR2 possessing an IC50 value of 0.89 µm. Structure activity relationship and molecular docking revealed the importance of substitution features of aryl group of aryllsulfonylimidazolidine-2,4-dione scaffold. It was observed that the substitution with a halogen at para position of the aryl group had a remarkable effect on ALR2 inhibition potency.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Imidazolidinas/síntese química , Imidazolidinas/farmacologia , Animais , Inibidores Enzimáticos/química , Hipoglicemiantes/química , Imidazolidinas/química , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular
20.
Cell Rep ; 11(2): 175-82, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25865881

RESUMO

Control over the frequency and pattern of neuronal spike discharge depends on Ca2+-gated K+ channels that reduce cell excitability by hyperpolarizing the membrane potential. The Ca2+-dependent slow afterhyperpolarization (sAHP) is one of the most prominent inhibitory responses in the brain, with sAHP amplitude linked to a host of circuit and behavioral functions, yet the channel that underlies the sAHP has defied identification for decades. Here, we show that intermediate-conductance Ca2+-dependent K+ (IKCa) channels underlie the sAHP generated by trains of synaptic input or postsynaptic stimuli in CA1 hippocampal pyramidal cells. These findings are significant in providing a molecular identity for the sAHP of central neurons that will identify pharmacological tools capable of potentially modifying the several behavioral or disease states associated with the sAHP.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Neurônios/fisiologia , Canais de Potássio Cálcio-Ativados/química , Células Piramidais/fisiologia , Potenciais de Ação/fisiologia , Animais , Região CA1 Hipocampal/química , Região CA1 Hipocampal/fisiologia , Polaridade Celular/fisiologia , Hipocampo/química , Hipocampo/fisiologia , Camundongos , Neurônios/química , Técnicas de Patch-Clamp , Canais de Potássio Cálcio-Ativados/metabolismo , Células Piramidais/química
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