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1.
Artigo em Inglês | MEDLINE | ID: mdl-34645380

RESUMO

BACKGROUND: Natural products from herbs are prolific to display robust anticancer activities. OBJECTIVES: In the current study, B-Raf kinase protein (PDB: 3OG7), a potent target for melanoma, was tested against two guaiane-type sesquiterpene dimers, xylopin E-F, obtained from Xylopia vielana. METHODS: In this work, a systematic in silico study using ADMET analysis, bioactivity score forecasts, molecular docking, and its simulations were conducted to understand compounds' pharmacological properties. RESULTS: During ADMET predictions of both the compounds, Xylopin E-F has displayed a safer profile in hepatotoxicity, cytochrome inhibition, and only xylopin F displayed as non-cardiotoxic compared to FDA approved drug vemurafenib. Both the compounds were proceeded to molecular docking experiments using Autodock docking software and both the compounds Xylopin E-F have displayed higher binding potential with -11.5Kcal/mol energy compared to control vemurafenib -10.2 Kcal/mol. All the compounds were further evaluated for their MD simulations and their molecular interactions with the B-Raf kinase complex displayed precise interactions with the active gorge of the enzyme by hydrogen bonding. CONCLUSIONS: Overall, xylopin F had a better profile relative to xylopin E and vemurafenib, and these findings indicated that this bio-molecule could be used as an anti-melanoma agent and as a possible anticancer drug in the future. Therefore, this is a systematic optimized in silico approach to creating an anticancer pathway for guaiane dimers against the backdrop of its potential for future drug development.

2.
Iran J Pharm Res ; 20(2): 206-228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34567157

RESUMO

Considering the diversified pharmacological importance of thiazole and triazole heterocyclic moieties, a unique series of S-aralkylated bi-heterocyclic hybrids, 7a-l, was synthesized in a convergent manner. The structures of newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, IR, and EI-MS spectral studies. The structure-activity relationship of these compounds was envisaged by analyzing their inhibitory effects against tyrosinase, whereby all these molecules exhibited potent inhibitory potentials relative to the standard used. The Kinetics mechanism was ascertained by Lineweaver-Burk plots, which revealed that 7g inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0057µM. These bi-heterocyclic molecules also disclosed good binding energy values (kcal /mol) when assessed computationally. So, these molecules can be considered promising medicinal scaffolds for the treatment of skin disorders.

3.
J Enzyme Inhib Med Chem ; 36(1): 1509-1520, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238110

RESUMO

In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC50 (µg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 µg/mL) compared to the reference drug acarbose (21.59 ± 1.5 µg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a non-competitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.


Assuntos
Antibacterianos/farmacologia , Compostos Azo/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , alfa-Glucosidases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Compostos Azo/síntese química , Compostos Azo/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Staphylococcus aureus/efeitos dos fármacos
4.
Sci Rep ; 11(1): 12256, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112868

RESUMO

Proteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer's disease. In the current study, a molecular docking approach was employed to explore the interactive behavior of TNFR1 and MADD proteins and their role in the activation of downstream signaling pathways. The computational sequential and structural conformational results revealed that Asp400, Arg58, Arg59 were common residues of TNFR1 and MADD which are involved in the activation of downstream signaling pathways. Aspartic acid in negatively charged residues is involved in the biosynthesis of protein. However, arginine is a positively charged residue with the potential to interact with oppositely charged amino acids. Furthermore, our molecular dynamic simulation results also ensured the stability of the backbone of TNFR1 and MADD death domains (DDs) in binding interactions. This DDs interaction mediates some conformational changes in TNFR1 which leads to the activation of mediators proteins in the cellular signaling pathways. Taken together, a better understanding of TNFR1 and MADD receptors and their activated signaling cascade may help treat Alzheimer's disease. The death domains of TNFR1 and MADD could be used as a novel pharmacological target for the treatment of Alzheimer's disease by inhibiting the MAPK pathway.

5.
Bioinform Biol Insights ; 15: 11779322211021430, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163151

RESUMO

Background: A recent COVID-19 pandemic has resulted in a large death toll rate globally and even no cure or vaccine has been successfully employed to combat this disease. Patients have been reported with multi-organ dysfunction along with acute respiratory distress syndrome which implies a critical situation for patients and made them difficult to breathe and survive. Moreover, pathology of COVID-19 is also related to cytokine storm which indicates the elevated levels of interleukin (IL)-1, IL-6, IL-12, and IL-18 along with tumor necrosis factor (TNF)-α. Among them, the proinflammatory cytokine IL-6 has been reported to be induced via binding of severe acute respiratory syndrome coronavirus 2 (SARS)-CoV-2 to the host receptors. Methodology: Interleukin-6 blockade has been proposed to constitute novel therapeutics against COVID-19. Thus, in this study, 15 phytocompounds with known antiviral activity have been subjected to test for their inhibitory effect on IL-6. Based on the affinity prediction, top 3 compounds (isoorientin, lupeol, and andrographolide) with best scores were selected for 50 ns molecular dynamics simulation and MMGB/PBSA binding free energy analysis. Results: Three phytocompounds including isoorientin, lupeol, and andrographolide have shown strong interactions with the targeted protein IL-6 with least binding energies (-7.1 to -7.7 kcal/mol). Drug-likeness and ADMET profiles of prioritized phytocompounds are also very prominsing and can be further tested to be potential IL-6 blockers and thus benficial for COVID-19 treatment. The moelcular dynamics simulation couple with MMGB/PBSA binding free energy estimation validated conformational stability of the ligands and stronger intermolecular binding. The mean RMSD of the complexes is as: IL6-isoorientin complex (3.97 Å ± 0.77), IL6-lupeol (3.97 Å ± 0.76), and IL6-andrographolide complex (3.96 Å ± 0.77). In addition, the stability observation was affirmed by compounds mean RMSD: isoorientin (0.72 Å ± 0.32), lupeol (mean 0.38 Å ± 0.08), and andrographolide (1.09 Å ± 0.49). A similar strong agreement on systems stability was unraveled by MMGB/PBSA that found net binding net ~ -20 kcal/mol for the complexes dominated by van der Waal interaction energy. Conclusion: It has been predicted that proposing potential IL-6 inhibitors with less side effects can help critical COVID-19 patients because it may control the cytokine storm, a major responsible factor of its pathogenesis. In this study, 3 potential phytocompounds have been proposed to have inhibitory effect on IL-6 that can be tested as potential therapeutic options against SARS-CoV-2.

6.
Bioorg Med Chem ; 41: 116222, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34058664

RESUMO

In this research work, we have designed and synthesized some biologically useful of 1,3,4-Oxadiazoles. The structural interpretation of the synthesized compounds has been validated by using FT-IR, LC-MS, HRMS, 1H NMR and 13C NMR techniques. Moreover, the in-vitro mushroom tyrosinase inhibitory potential of the target compounds was assessed. The in-vitro study reveals that, all compounds demonstrate an excellent tyrosinase inhibitory activity. Especially, 2-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-ylthio)-N-phenylacetamide (IC50 = 0.003 ± 0.00 µM) confirms much more significant potent inhibition activity compared with standard drug kojic acid (IC50 = 16.83 ± 1.16 µM). Subsequently, the most potent five oxadiazole compounds were screened for cytotoxicity study against B16F10 melanoma cells using an MTT assay method. The survival rate for the most potent compound was more pleasant than other compounds. Furthermore, the western blot results proved that the most potent compound considerably decreased the expression level of tyrosinase at 50 µM (P < 0.05). The molecular docking investigation exposed that the utmost potent compound displayed the significant interactions pattern within the active region of the tyrosinase enzyme and which might be responsible for the decent inhibitory activity towards the enzyme. A molecular dynamic simulation experiment was presented to recognize the residual backbone stability of protein structure.

7.
J Biomol Struct Dyn ; : 1-10, 2020 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-33342351

RESUMO

Tyrosinase is a multi-copper enzyme found in plants, animals and microorganisms, plays a critical role in the melanogenesis and browning process critical to cosmetics and food industries. Many natural, semi-synthetic and synthetic inhibitors have been discovered. To this end, a small library of symmetrical Bis-Azo-Azamethine hybrids 5a-j was synthesized and characterized through spectroscopic and analytical data and explored for mushroom tyrosinase and free radical scavenging activity. All of the molecules 5a-j explicated better potential compared to the standard Kojic acid. On the whole, compound 5i having IC50 value 0.002 ± 0.004 µM was found to be the most potent derivative. The Kinetic studies were performed for 5i and indicating the mode of inhibition in a competitive manner. Structure Activity Relationship (SAR) analysis and docking studies were carried out. Thus compound 5i bearing bulky naphthyl groups was most potent and, The molecular docking indicated formation of two hydrogen bonds with Arg268 and one hydrophobic interaction with Glu322. The carbonyl oxygen of 5i interacts with Arg268 and form two hydrogen bonds having lengths 2.44 and 2.62 Å, respectively. In the same way, compounds 5a-j were appraised for DPPH free radical scavenging ability and five of them 5d, 5e, 5h, 5i and 5j were found to exhibit higher % scavenging potency compared with vitamin C, as the standard. Interesting compound 5i was again the most potent in the series. The current investigation points towards the role of naphthyl group in design of new inhibitors of melanogenesis and the antioxidants with improved efficacy.Communicated by Ramaswamy H. Sarma.

8.
Iran J Pharm Res ; 19(1): 487-506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922502

RESUMO

The synthesis of a novel series of bi-heterocyclic propanamides, 7a-l, was accomplished by S-substitution of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol (3). The synthesis was initiated from ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (1) which was converted to corresponding hydrazide, 2, by hydrazine hydrate in methanol. The refluxing of hydrazide, 2, with carbon disulfide in basic medium, resulted in 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol (3). A series of electrophiles, 6a-l, was synthesized by stirring un/substituted anilines (4a-l) with 3-bromopropanoyl chloride (5) in a basic aqueous medium. Finally, the targeted compounds, 7a-l, were acquired by stirring 3 with newly synthesized electrophiles, 6a-l, in DMF using LiH as a base and an activator. The structures of these bi-heterocyclic propanamides were confirmed through spectroscopic techniques, such as IR, 1H-NMR, 13C-NMR, and EI-MS. These molecules were tested for their urease inhibitory potential, whereby, the whole series exhibited very promising activity against this enzyme. Their cytotoxic behavior was ascertained through hemolysis and it was observed that all these were less cytotoxic agents. The in-silico molecular docking analysis of these molecules was also in full agreement with their in-vitro enzyme inhibition data.

9.
J Biomol Struct Dyn ; : 1-10, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924784

RESUMO

Proteins are key player in the prognosis and therapeutics of carcinomas through the interactions of downstream signalling cascades. Current work insight the structural and mutational analysis of DACH1 in association with carcinogenesis. The homology modelling was employed to predict mutant and wild protein models and their reliability and accuracy was verified through multiple online approaches. Furthermore, MD simulation technique was employed to check the mutation effects on the stability of DACH1 through root mean square deviation and fluctuation graphs. Our results proposed that DACH1 mutation (C188Y) may cause lethal effects and can disturb the DACH1 structure. The observed mutational results showed that C188Y may cause some lethal effect in human body. Based on aforementioned computational assessments, it has concluded that DACH1 could be used as good therapeutic target in the prognosis and therapeutic of carcinoma insurgence.Communicated by Ramaswamy H. Sarma.

10.
J Biomol Struct Dyn ; : 1-9, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32762529

RESUMO

Herein, we report synthesis of a set of benzothiazole-thiourea hybrids with aromatic and aliphatic side chains (BT1 to BT9) using an elegant synthetic strategy. The newly synthesized benzothiazole-thiourea conjugates were subjected to In-vitro tyrosinase inhibition and free radical scavenging activity. Majority of the compounds indicated inhibition considerably improved than the standard; compound (Kojic acid with IC50 = 16.8320 ± 1.1600 µM) BT2 with IC50 = 1.3431 ± 0.0254 µM was found to be the best inhibitor. A non-competitive mode of inhibition of BT2 was disclosed with Ki value of 2.8 µM. In order to study enzyme-inhibitor interactions SAR analysis molecular docking was carried out. The amino groups of thiourea were involved in hydrogen bonding with Glu322 showing the bond length of 1.74 and 2.70 Å, respectively. Moreover, the coupling of π-π was displayed between benzothiazole and benzene rings of His244 and His263, respectively. The outcome of this study might help to develop new inhibitors of melanogenesis, important for cosmetic and food products. Communicated by Ramaswamy H. Sarma.

11.
Mol Divers ; 2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32862361

RESUMO

The work presented in this paper aims toward the synthesis of aryl thiourea derivatives 4a-l of pyrazole based nonsteroidal anti-inflammatory drug named 4-aminophenazone, as potential inhibitors of intestinal alkaline phosphatase enzyme. The screening of synthesized target compounds 4a-l for unraveling the anti-inflammatory potential against calf intestinal alkaline phosphatase gives rise to lead member 4c possessing IC50 value 0.420 ± 0.012 µM, many folds better than reference standard used (KH2PO4 IC50 = 2.8 ± 0.06 µM and L-phenylalanine IC50 = 100 ± 3.1 µM). SAR for unfolding the active site binding pocket interaction along with the mode of enzyme inhibition based on kinetic studies is carried out which showed non-competitive binding mode. The enzyme inhibition studies were further supplemented by molecular dynamic simulations for predicting the protein behavior against active inhibitors 4c and 4g during docking analysis. The preliminary toxicity of the synthesized compounds was determined by using brine shrimp assay. This work also includes detailed biochemical analysis along with RO5 parameters for all the newly synthesized drug derivatives 4a-l.

12.
Spectrochim Acta A Mol Biomol Spectrosc ; 241: 118667, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32693367

RESUMO

In this work, a series of the rhodamine 6G based derivatives 5a-5g, were synthesized. The structural framework of the synthesized compounds was established by using 1H NMR, 13C NMR, FT-IR, and LC-MS analytical methods. The spectroscopic properties of the target compounds were determined by using absorption and fluorescence study in four different solvents. Furthermore, the synthesized derivatives were assessed for in-vitro screening against jack bean urease inhibition and in-silico molecular docking study. The result reveals that all the compounds exhibit good urease inhibitory activity against this enzyme but among the series, the compound 5a &5c with an IC50 values of 0.1108 ±â€¯0.0038 µM and 0.1136 ±â€¯0.0295 µM shows to be most auspicious inhibitory activity compared to a standard drug (Thiourea) having IC50 value 4.7201 ±â€¯0.0546 µM. Subsequently, the molecular docking experiment was analysed to distinguish the enzyme-inhibitor binding interaction.


Assuntos
Urease , Xantenos , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade
13.
Genes Genomics ; 42(8): 847-854, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32506268

RESUMO

BACKGROUND: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare skeletal dysplasia following autosomal recessive mode of inheritance and characterized by abnormal growth plates, short and abnormal bones in the extremities and spine. OBJECTIVE: Present study was designed to report the molecular basis of AMDM in enrolled consanguineous family from Pakistan. METHODS: A consanguineous family from Vehari District in Pakistan having multiple siblings suffering from AMDM was enrolled in present study. Whole exome sequencing (WES) approach was adopted to identify causative agent of AMDM. Human full length NPR2 gene and sequence with nonsense mutation was amplified by using Myc-tagged pXN vector and transformed in E. coli DH5α cells to confirm mutation. SDS-PAGE and Western blotting were done to confirm the production of truncated protein. Computational three dimensional structure generation through homology modeling approach was done to compare protein structure between patients and controls. RESULTS: WES reveled a nonsense mutation (c.613 C>T, p.R205X) in exon 1 of NPR2 gene leading to premature termination codon in mRNA of NPR2 gene resulting in a truncated protein with 204 amino acid residues that was confirmed by SDS-PAGE and Western blotting. Sanger sequencing confirmed that mutation in all subjects and mutation followed Mendalian pattern of inheritance. Multiple sequence alignment by ClustalW revealed that mutated domain of NPR2 is conserved region. Proetin structure comparison revealed a significant structural part of NPR2 was missing in truncated protein as compared to control. CONCLUSION: We are reporting that a novel nonsense mutation (c.613 C>T, p.R205X) in exon 1 of NPR2 gene is causing AMDM in a consanguineous Pakistani family.


Assuntos
Códon sem Sentido , Nanismo/genética , Osteocondrodisplasias/genética , Receptores do Fator Natriurético Atrial/genética , Consanguinidade , Nanismo/sangue , Escherichia coli , Feminino , Células HEK293 , Humanos , Masculino , Osteocondrodisplasias/sangue , Paquistão , Linhagem , Fenótipo , Reação em Cadeia da Polimerase/métodos , Receptores do Fator Natriurético Atrial/sangue , Sequenciamento Completo do Exoma/métodos
14.
Mol Divers ; 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32399854

RESUMO

We have created a novel series of mushroom tyrosinase inhibitors with 1,2,4-triazole as fundamental skeleton. The target compound 1,2,4-triazol-3-ylthio)-N-phenyl acetamide derivatives 9(a-l) were synthesized by the reaction of 4- and 5-substituted 1,2,4-triazole-3-thiol derivatives 6(a-c) with 2-chloro-N-sub/un-substituted phenyl acetamide derivatives 8(a-d) under basic condition. By using the analytical techniques for instance, FTIR, LC-MS, 1H NMR and 13C NMR, the structural verification was evaluated. The novel series of the target compounds 9(a-l) has been scanned for biological activity (mushroom tyrosinase inhibition potential) which demonstrates adequate results. Interestingly, compound 9k (IC50 = 0.0048 ± 0.0016 µM) exhibits 3500 times more activity compared with standard drug kojic acid (IC50 = 16.8320 ± 1.1600 µM) against mushroom tyrosinase inhibitor. Furthermore, the cytotoxicity experiment was carried out for the highly effective target compounds (9d, 9i, 9j and 9k) by using MTT assay method for A375 human melanoma cells to define the nontoxic performance of the most effective compounds ranging from 1 to 25 µM. Furthermore, the molecular docking study delivers the thought concerning the interface of the ligand with an enzyme. Also, the dynamic simulation was accomplished for compound 9k to govern the plausible binding model.

15.
Bioorg Chem ; 100: 103906, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422387

RESUMO

A new series of 4H-chromene-3-carboxylate derivatives were synthesized using multicomponent reaction of salicylaldehyde, ethyl acetoacetate and dimedone in ethanol with K3PO4 as a catalyst at 80 °C. The structures of all newly synthesized compounds were confirmed by spectral techniques viz. IR, 1H NMR, 13C NMR, and LCMS analysis. The newly synthesized compounds 4a to 4j were screened against elastase enzyme. Interestingly, all these compounds found to be potent elastase inhibitors with much lower IC50 value. The compound 4b was found to be most potent elastase inhibitor (IC50 = 0.41 ± 0.01 µM) amongst the synthesized series against standard Oleanolic Acid (IC50 value = 13.45 ± 0.0 µM). The Kinetics mechanism for compound 4b was analyzed by Lineweaver-Burk plots which revealed that compound inhibited elastase competitively by forming an enzyme-inhibitor complex. Along with this, all the synthesized compounds (4a - 4j) exhibits excellent DPPH free radical scavenging ability. The inhibition constant Ki for compound 4b was found to be 0.6 µM. The computational study was comprehensible with the experimental results with good docking energy values (Kcal/mol). Therefore, these molecules can be considered as promising medicinal scaffolds for the treatment of skin-related maladies.


Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Elastase Pancreática/antagonistas & inibidores , Animais , Benzopiranos/síntese química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Quimioinformática , Inibidores Enzimáticos/síntese química , Simulação de Acoplamento Molecular , Pâncreas/enzimologia , Elastase Pancreática/química , Elastase Pancreática/metabolismo , Suínos
16.
Eur J Med Genet ; 63(8): 103958, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32470407

RESUMO

Spondylo-epimetaphyseal dysplasia Matrilin 3 type (SEMD) is a rare autosomal recessive skeletal dysplasia characterized by short stature, abnormalities in the vertebral bodies and long bones, especially the lower limbs. We enrolled a consanguineous family from Pakistan in which multiple siblings suffered from severe skeletal dysplasia. The six affected subjects ranged in heights from 100 to 136 cm (~-6 standard deviation). Lower limb abnormalities with variable varus and valgus deformities and joint dysplasia were predominant features of the clinical presentation. Whole exome sequencing (WES) followed by Sanger sequencing identified a missense variant, c.542G > A, p.(Arg181Gln) in MATN3 as the genetic cause of the disorder. The variant was homozygous in all affected individuals while the obligate carriers had normal heights with no skeletal symptoms, consistent with a recessive pattern of inheritance. Multiple sequence alignment revealed that MATN3 domain affected by the variant is highly conserved in orthologous proteins. The c.542G > A, p.(Arg181Gln) variant is only the fourth variant in MATN3 causing an autosomal recessive disorder and thus expands the genotypic spectrum.


Assuntos
Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Consanguinidade , Feminino , Homozigoto , Humanos , Masculino , Proteínas Matrilinas/química , Proteínas Matrilinas/genética , Osteocondrodisplasias/patologia , Linhagem , Domínios Proteicos
17.
Biomed Res Int ; 2020: 8104107, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149140

RESUMO

A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC500.84 ± 0.12 µM among all other derivatives and is also more active than standard acetazolamide (IC500.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with K i value 8.6 µM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.


Assuntos
Inibidores da Anidrase Carbônica , Bases de Schiff , Sulfonamidas , Acetazolamida , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Cinética , Células MCF-7 , Simulação de Acoplamento Molecular
18.
Med Chem ; 16(2): 229-243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31309895

RESUMO

BACKGROUND: Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems. OBJECTIVE: This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors. METHODS: Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined. RESULTS: It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation. CONCLUSIONS: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.


Assuntos
Aminocumarinas/síntese química , Aminocumarinas/farmacologia , Canavalia/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Urease/antagonistas & inibidores , Aminocumarinas/química , Aminocumarinas/metabolismo , Animais , Artemia , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Conformação Proteica , Urease/química , Urease/metabolismo
19.
Bioorg Chem ; 94: 103445, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826809

RESUMO

In the current research work, different N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides have been synthesized according to the protocol described in scheme 1. The synthesis was initiated by reacting various substituted anilines (1a-e) with 4-chlorobutanoyl chloride (2) in aqueous basic medium to give various electrophiles, 4-chloro-N-(substituted-phenyl)butanamides (3a-e). These electrophiles were then coupled with 1-[(E)-3-phenyl-2-propenyl]piperazine (4) in polar aprotic medium to attain the targeted N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides (5a-e). The structures of all derivatives were identified and characterized by proton-nuclear magnetic resonance (1H NMR), carbon-nuclear magnetic resonance (13C NMR) and Infra-Red (IR) spectral data along with CHN analysis. The in vitro inhibitory potential of these butanamides was evaluated against Mushroom tyrosinase, whereby all compounds were found to be biologically active. Among them, 5b exhibited highest inhibitory potential with IC50 value of 0.013 ± 0.001 µM. The same compound 5b was also assayed through in vivo approach, and it was explored that it significantly reduced the pigments in zebrafish. The in silico studies were also in agreement with aforesaid results. Moreover, these molecules were profiled for their cytotoxicity through hemolytic activity, and it was found that except 5e, all other compounds showed minimal toxicity. The compound 5a also exhibited comparable results. Hence, some of these compounds might be worthy candidates for the formulation and development of depigmentation drugs with minimum side effects.


Assuntos
Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Melaninas/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Piperazina/farmacologia , Amidas/síntese química , Amidas/química , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Melaninas/metabolismo , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Piperazina/síntese química , Piperazina/química , Relação Estrutura-Atividade , Peixe-Zebra
20.
Mol Divers ; 24(4): 1185-1203, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31396774

RESUMO

We have designed and synthesized a novel acidic ionic liquid and explored its catalytic efficiency for the synthesis of 1,2,4-triazolidine-3-thione derivatives. A simple reaction between aldehydes and thiosemicarbazide for short time in 60:40 v/v water/ethanol at room temperature offers target 1,2,4-triazolidine-3-thione derivatives. The formation of target compounds is confirmed by NMR, IR and ESI-MS analysis. Pleasingly, synthesized compounds show noteworthy acetylcholinesterase (AChE) inhibitory activity with much lower IC50 values 0.0269 ± 0.0021-1.1725 ± 0.0112 µM than standard Neostigmine methylsulphate. In addition, synthesized 1,2,4-triazolidine-3-thiones exhibits significant free radical scavenging activity as compared to standard vitamin C. The studies on validation of Lipinski's rule through chemoinformatics properties and molecular docking analysis are in support of in vitro analysis. Therefore, overall present study illustrates synthesis of some new 1,2,4-triazolidines-3-thiones which can serve as a template for drug designing such as AChE inhibitors. Herein, we proposed ionic liquid-catalyzed ease of synthetic approach for medicinally important 1,2,4-triazolidine-3-thiones and their bio-evaluations.

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