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In this study we presented a novel series of NNO tridentate ligands generating imino, amido and oxo donor pocket for Pd(II) coordination. All the compounds were meticulously characterized by elemental analysis and advanced spectroscopic techniques, including FTIR, proton and carbon NMR. The synthesized compounds underwent rigorous evaluation for their potential as anti-cancer agents, utilizing the aggressive breast cancer cell lines MDA-MB (ATCC) and MCF-7 as a crucial model for assessing growth inhibition in cancer cells. Remarkably, the MTT assay unveiled the robust anti-cancer activity for all palladium complexes against MDA-MB-231 and MCF-7 cells. Particularly, complex [Pd(L1)(CH3CN)] exhibited exceptional potency with an IC50 value of 25.50 ± 0.30 µM (MDA-MB-231) and 20.76 ± 0.30 µM (MCF-7), compared to respective 27.00 ± 0.80 µM and 24.10 ± 0.80 µM for cisplatin, underscoring its promising therapeutic potential. Furthermore, to elucidate the mechanistic basis for the anti-cancer effects, molecular docking studies on tyrosine kinases, an integral target in cancer research, were carried out. The outcome of these investigations further substantiated the remarkable anticancer properties inherent to these innovative compounds. This research offers a compelling perspective on the development of potent anti-cancer agents rooted in the synergy between ligands and Pd(II) complexes and presenting a promising avenue for future cancer therapy endeavors.
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Zeolitic Imidazolate Framework-8 (ZIF-8) material was prepared by chemical precipitation method. The microstructure and physical properties of the as-prepared samples were characterized by XRD, BET, FESEM and UV spectrophotometer. The self-made four-channel measurement device was used to test the gas sensitivity of ZIF-8 material toward ethanol gas under photo-thermal synergistic excitation. The results showed that the sample was typical ZIF-8 (Eg = 4.96 eV) with a regular dodecahedron shape and the specific surface is up to 1793 m2/g. The as-prepared ZIF-8 has a gas response value of 55.04 to 100 ppm ethanol at 75°C and it shows good gas sensing selectivity and repeated stability. The excellent gas sensitivity can be attributed to the increase of free electron concentration in the ZIF-8 conduction band by photo-thermal synergistic excitation, and the large specific surface area of ZIF-8 material provides more active sites for gas-solid surface reaction. The reaction mechanism of ZIF-8 material under multi-field excitation was also discussed.
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Imidazóis , Zeolitas , Temperatura , Zeolitas/química , Temperatura BaixaRESUMO
Twenty surface sediment samples were gathered from Chasma Lake, deciding the radionuclides 137Cs, 226Ra, 228Ra, 232Th, and 40K and their associated hazard indices. The deliberate radionuclide activities of present research have been contrasted with earlier research, and acquired outcomes in the present study are found below the results in the world. The radiation hazard indices following the presence of natural radionuclides in sediment samples were estimated, and the results assigned the values of all the determined radiological indices found inside the worldwide suggested limits. It was concluded from the current review that the sediment of Chashma Lake is safe for construction and agriculture and does not make radiation dangerous to the nearby local area of the lake.
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Monitoramento Ambiental , Lagos , Paquistão , AgriculturaRESUMO
During the present investigation, two new sulfonamide-based Schiff base ligands, 4-{[(2-hydroxy-3-methoxyphenyl)methylidene]amino}-N-(1,3-thiazol-2-yl)benzene-1-sulfonamide (L1) and 4-{[1-(2-hydroxyphenyl)ethylidene]amino}-N-(1,3-thiazol-2-yl)benzene-1-sulfonamide (L2), have been synthesized and coordinated with the transition metals (V, Fe, Co, Ni, Cu and Zn). The ligands were characterized by their physical (color, melting point, yield and solubility), spectral (UV-Vis, FT-IR, LC-MS, 1H NMR and 13C NMR) and elemental data. The structures of the metal complexes (1)-(12) were evaluated through their physical (magnetic and conductance), spectral (UV-Vis, FT-IR and LC-MS) and elemental data. The molecular geometries of ligands and their selected metal complexes were optimized at their ground state energies by B3LYP level of density functional theory (DFT) utilizing 6-311+G (d, p) and LanL2DZ basis set. The first principle study has been discussed for the electronic properties, the molecular electrostatic possibilities as well as the quantum chemical identifiers. An obvious transition of intramolecular charge had been ascertained from the occupied to the unoccupied molecular orbitals. The UV-Vis analysis was performed through time-dependent density functional theory (TD-DFT) by CAM-B3LYP/6-311+G (d, p) function. The in vitro antimicrobial activity was studied against two fungal (Aspergillus niger and Aspergillus flavus) and four bacterial (Staphylococcus aureus, Klebsiela pneumoniae, Escherichia coli and Bacillus subtilis) species. The antioxidant activity was executed as antiradical DPPH scavenging activity (%), total iron reducing power (%) and total phenolic contents (mg GAE g-1). Additionally, enzyme inhibition activity was done against four enzymes (Protease, α-Amylase, Acetylcholinesterase and Butyrylcholinesterase). All the synthetic products exhibited significant bioactivity which were found to enhance upon chelation due to phenomenon of charge transfer from metal to ligand.
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Anti-Infecciosos , Preparações Farmacêuticas , Acetilcolinesterase , Anti-Infecciosos/farmacologia , Butirilcolinesterase , Ligantes , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The concept of the internet of things (IoT) motivates us to connect bulk isolated heterogeneous devices to automate report generation without human interaction. Energy-efficient routing algorithms help to prolong the network lifetime of these energy-restricted smart devices that are connected by means of wireless sensor networks (WSNs). Current vendor-level advancements enable algorithm-level flexibility to design protocols to concurrently collect multiple application data while enforcing the reduction of energy expenditure to gain commercial success in the industrial stage. In this paper, we propose a hybrid clustering and routing algorithm with threshold-based data collection for heterogeneous wireless sensor networks. In our proposed model, homogeneous and heterogeneous nodes are deployed within specific regions. To reduce unnecessary data transmission, threshold-based conditions are presented to prevent unnecessary transmission when minor or no change is observed in the simulated and real-world applications. We further extend our proposed multi-hop model to achieve more network stability in dense and larger network areas. Our proposed model shows enhancement in terms of load balancing and end-to-end delay as compared to the other threshold-based energy-efficient routing protocols, such as the threshold-sensitive stable election protocol (TSEP), threshold distributed energy-efficient clustering (TDEEC), low-energy adaptive clustering hierarchy (LEACH), and energy-efficient sensor network (TEEN).
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Schiff bases are a class of organic compounds with azomethine moiety, exhibiting a wide range of biological potentials. In this research, six chiral Schiff bases, three 'S' series (H1−H3) and three 'R' series (H4−H6), were synthesized. The reaction was neat, which means without a solvent, and occurred at room temperature with a high product yield. The synthesized compounds were evaluated for analgesic potential in vivo at doses of 12.5 and 25 mg/kg using acetic-acid-induced writhing assay, formalin test, tail immersion and hot plate models, followed by investigating the possible involvement of opioid receptors. The compounds H2 and H3 significantly (*** p < 0.001) reduced the writhing frequency, and H3 and H5 significantly (*** p < 0.001) reduced pain in both phases of the formalin test. The compounds H2 and H5 significantly (*** p < 0.001) increased latency at 90 min in tail immersion, while H2 significantly (*** p < 0.001) increased latency at 90 min in the hot plate test. The 'S' series Schiff bases, H1−H3, were found more potent than the 'R' series compounds, H4−H6. The possible involvement of opioid receptors was also surveyed utilizing naloxone in tail immersion and hot plate models, investigating the involvement of opioid receptors. The synthesized compounds could be used as alternative analgesic agents subjected to further evaluation in other animal models to confirm the observed biological potential.
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Extratos Vegetais , Bases de Schiff , Analgésicos/uso terapêutico , Animais , Dor/tratamento farmacológico , Extratos Vegetais/farmacologia , Receptores Opioides , Bases de Schiff/farmacologiaRESUMO
This study is concentrated on the radiological risk assessment of sixteen surface sediment samples recovered from Namal Lake, District Mianwali, Punjab, Pakistan. The activity of 137Cs, 40 K, 226Ra, 228Ra, and 232Th was carried out with the help of a high purity germanium detector (HPGe) in the sediment, varied in the ranges of > 0.02-3.73 ± 1.31, 98.32 ± 21.45-341.02 ± 58.67, 18.34 ± 2.16-34.23 ± 4.34, 1.62 ± .30-2.34 ± .52, and 0.14 ± 0.10-2.34 ± 0.59 Bq kg-1 with average values 0.74 ± 0.29, 237.26 ± 37.97, 25.06 ± 4.74, 1.97 ± 0.39, and 1.73 ± 0.33 Bq kg-1, respectively. The measured concentrations in the current study have been compared with other earlier studies in the world. The data was also used for determining the other useful parameters like radium equivalent activity, absorbed dose rate, annual effective dose rate, and external and internal hazards index to assess the radiological risk assessment for the environment around the study area. The ERICA Tool software was also applied for radiological risk assessment for lake fish due to the radioactivity present in the lake sediments. It was concluded from the results of ERICA tool that the risk quotient in this study is less than one indicating that no toxic effects of radioactivity for Namal Lake fish.
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Monitoramento de Radiação , Rádio (Elemento) , Poluentes Radioativos do Solo , Animais , Lagos , Paquistão , Radioisótopos de Potássio/análise , Monitoramento de Radiação/métodos , Rádio (Elemento)/análise , Medição de Risco , Poluentes Radioativos do Solo/análise , Espectrometria gama , Tório/análiseRESUMO
Background: Several authors investigated a dosimetric impact of leaf width on radiotherapy plan quality subjectively, and concluded that thinner leaf-width multileaf collimators (MLC) are beneficial because of their better coverage of clinically relevant structures. Study aimed to investigate the dosimetric effect of MLC leaf width on volumetric modulated arc therapy plan quality by objective approach. Materials and methods: Twelve of each prostate and head-and-neck patients were planned for volumetric modulated arc therapy (VMAT) treatments for MLC leaf widths of 4 mm and 10 mm. Three different VMAT schemes single-arc, dual-arc and two combined independent single-arcs were optimized. Dose volume histogram and Isodose distribution were used for quantitative and qualitative comparison of the treatment plan, respectively. Dose-volume-indices of the planning target volume, organs at risk and number of delivered monitor units were compared. The 4 mm leaf width being reference over 10 mm and results were noted as statistically significant if p ≤ 0.05 using student t-test. Results: All VMAT schemes for both tumor sites showed a gain in target coverage, similar organs at risk doses and higher monitor units to be delivered, when changing leaf width from 10 mm to 4 mm. The p-values were significant for majority of head-and-neck dose indices. Conclusion: The thinner-leaf MLCs, owing to their better spatial resolution, result in an overall gain for target coverage, while maintaining permissible doses to the organs at risk.
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The present study describes the discovery of novel inhibitors of mushroom tyrosinase enzyme. For that purpose, a series of varyingly substituted 2-phenylchromone analogues 1-28 were synthesized and characterized in detail by various spectroscopic techniques (UV-Vis, FTIR, 1H NMR, 13C NMR) and mass spectrometry. All the derivatives (1-28) were screened in vitro for their inhibitory potential against mushroom tyrosinase enzyme. Interestingly, all the synthetic compounds displayed good to excellent inhibitory activity with IC50 values ranging from 0.093 ± 0.003 µg/ml to 23.58 ± 0.94 µg/ml for brominated 3-hydroxy-2-phenylchromones and 0.22 ± 0.017 µg/ml to 22.22 ± 1.1 µg/ml for brominated 2-phenylchromones against tyrosinase in comparison to the standard kojic acid (IC50 = 1.79 ± 0.64 µg/ml). Remarkably, the bromine atoms attached on ring A attribute to increases the inhibitory potential of 2-phenylchromone moiety and anti-tyrosinase assay demonstrated that compound 10 (IC50 = 0.093 ± 0.003 µg/ml) was found almost nineteenfold, 11 (IC50 = 0.126 ± 0.015 µg/ml) fourteenfold and 26 (IC50 = 0.22 ± 0.017 µg/ml) about eightfold more active than the positive control. Notably, among the already literature reported tyrosinase inhibitors, these analogues have been found the most active inhibitors of mushroom tyrosinase with the lowest possible IC50 values. To design and develop novel tyrosinase inhibitors using 2-phenylchromone as a structural motif in the future, a limited structure-activity relationship was established. Moreover, in silico studies were carried out to rationalize the binding mode of interactions of all the targeted compounds (1-28) with the active site of enzymes. The experimental and theoretical results are in parallel with one another. In addition, molecular description was performed with the drug-likeness and bioactivity scores. Computational analysis predicted that few compounds are in a linear correlation with Lipinski's RO5 indicating superb drug-likeness and bioactivity score for drug targets.
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Cromonas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To evaluate different VMAT planning techniques for a multi-leaf collimator (MLC)providing maximum aperture of 21 × 16 cm². METHODS: A VMAT planning study of nine prostate and nine head-and-neck cancer patients was carried out. The patients were previously treated with Intensity Modulated Radiotherapy (IMRT) technique during 2014-15, at radiation oncology SanBortolo Hospital, Vicenza, Italy. Three VMAT plans for each of prostate and head-and-neck cancer patient were optimized using Pinnacle treatment planning system for 6MV photon beam from ElektaSynergyS®Linac system. Single arc, dual arc and combined two independent-single-arcs were optimized for collimator angle 45°. VMAT treatment planning comparison was made among single-arc dual-arc and combined two independent-single-arcs. The student's t-test (two-sided) with p ≤ 0.05 was applied for significant difference between dose volume indices of plans. RESULTS: All VMAT techniques produced clinically acceptable plans for prostate, while for head-and-neck, DA and ISAs significantly improved target coverage compared to SA. Single arc is sufficient for prostate, while inefficient in case of head-and-neck dose-planning. In spite of having different VMAT optimization approach dual arc and two combined independent-single-arcs provided very similar target coverage, while dual arc improved sparing of organs-at-risk. Similar treatment delivery times were observed for DA and ISAs VMAT techniques. CONCLUSIONS: Single arc is sufficient for prostate, while inefficient in case of head-and-neck dose-planning. Dual arc and two combined independent-single-arcs provided similar PTV coverage, while DA provided better sparing of organs at risk.
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Neoplasias de Cabeça e Pescoço , Radioterapia de Intensidade Modulada , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Masculino , Próstata , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por ComputadorRESUMO
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.
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Vírus da Dengue/enzimologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Ftalimidas/química , Ftalimidas/farmacologia , Inibidores de Proteases/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítio Alostérico , Antivirais/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Análise Espectral/métodos , Sulfonamidas/síntese química , BenzenossulfonamidasRESUMO
To explore new scaffolds for the treat of Alzheimer's disease appears to be an inspiring goal. In this context, a series of varyingly substituted flavonols and 4-thioflavonols have been designed and synthesized efficiently. All the newly synthesized compounds were characterized unambiguously by common spectroscopic techniques (IR, 1H-, 13C NMR) and mass spectrometry (EI-MS). All the derivatives (1-24) were evaluated in vitro for their inhibitory potential against cholinesterase enzymes. The results exhibited that these derivatives were potent selective inhibitors of acetylcholinesterase (AChE), except the compound 11 which was selective inhibitor of butyrylcholinesterase (BChE), with varying degree of IC50 values. Remarkably, the compounds 20 and 23 have been found the most potent almost dual inhibitors of AChE and BChE amongst the series with IC50 values even less than the standard drug. The experimental results in silico were further validated by molecular docking studies in order to find their binding modes with the active pockets of AChE and BChE enzymes.
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Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Flavonóis/química , Acetilcolinesterase/química , Butirilcolinesterase/química , Domínio Catalítico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Flavonóis/síntese química , Flavonóis/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
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.
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Hidrocarbonetos Fluorados/farmacologia , Elastase Pancreática/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Serina 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 Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , SuínosRESUMO
The prime objective of this research work is to prepare readily soluble synthetic analogues of naturally occurring 3-O-flavonol glycosides and then investigate the influence of various substituents on biological properties of synthetic compounds. In this context, a series of varyingly substituted 3-O-flavonol glycosides have been designed, synthesized and characterized efficiently. The structures of synthetic molecules were unambiguously corroborated by IR, 1H, 13C NMR and ESI-MS spectroscopic techniques. The structure of compound 22 was also analyzed by X-ray diffraction analysis. All the synthetic compounds (21-30) were evaluated for in vitro inhibitory potential against cholinesterase enzymes. The results displayed that most of the derivatives were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with varying degree of IC50 values. The experimental results were further encouraged by molecular docking studies in order to explore their binding behavior with the active pocket of AChE and BChE enzymes. The experimental and theoretical results are in parallel with one another.
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Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Glicosídeos/química , Acetilcolinesterase/química , Sítios de Ligação , Butirilcolinesterase/química , Inibidores da Colinesterase/metabolismo , Cristalografia por Raios X , Flavonóis/química , Flavonóis/metabolismo , Glicosídeos/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , TermodinâmicaRESUMO
AIM: The aim of study was to evaluate the dosimetric effect of collimator-rotation on VMAT plan quality, when using limited aperture multileaf collimator of Elekta Beam Modulator™ providing a maximum aperture of 21 cm × 16 cm. BACKGROUND: The increased use of VMAT technique to deliver IMRT from conventional to very specialized treatments present a challenge in plan optimization. In this study VMAT plans were optimized for prostate and head and neck cancers using Elekta Beam-ModulatorTM, whereas previous studies were reported for conventional Linac aperture. MATERIALS AND METHODS: VMAT plans for nine of each prostate and head-and-neck cancer patients were produced using the 6 MV photon beam for Elekta-SynergyS® Linac using Pinnacle3 treatment planning system. Single arc, dual arc and two combined independent-single arcs were optimized for collimator angles (C) 0°, 90° and 0°-90° (0°-90°; i.e. the first-arc was assigned C0° and second-arc was assigned C90°). A treatment plan comparison was performed among C0°, C90° and C(0°-90°) for single-arc dual-arc and two independent-single-arcs VMAT techniques to evaluate the influence of extreme collimator rotations (C0° and 90°) on VMAT plan quality. Plan evaluation criteria included the target coverage, conformity index, homogeneity index and doses to organs at risk. A 'two-sided student t-test' (p ≤ 0.05) was used to determine if there was a significant difference in dose volume indices of plans. RESULTS: For both prostate and head-and-neck, plan quality at collimator angles C0° and C(0°-90°) was clinically acceptable for all VMAT-techniques, except SA for head-and-neck. Poorer target coverage, higher normal tissue doses and significant p-values were observed for collimator angle 90° when compared with C0° and C(0°-90°). CONCLUSIONS: A collimator rotation of 0° provided significantly better target coverage and sparing of organs-at-risk than a collimator rotation of 90° for all VMAT techniques.
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The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson's reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE.
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Acetilcolinesterase/metabolismo , Benzofuranos/química , Benzofuranos/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Benzofuranos/síntese química , Butirilcolinesterase/química , Inibidores da Colinesterase/síntese química , Humanos , Simulação de Acoplamento Molecular , TermodinâmicaRESUMO
In this study, a series of novel bis-pyrimidine derivatives (1P-8P) were designed, synthesized, characterized, and investigated for their in vitro inhibitory activity against mushroom tyrosinase, an enzyme critical in melanin biosynthesis and implicated in various hyperpigmentation disorders. To the best of our knowledge, the bispyrimidine scaffold has been evaluated for the first time for its tyrosinase inhibitory activity. Their inhibitory activities were assessed, revealing inhibition with IC50 values in the micromolar range. Additionally, this series of compounds were found to inhibit tyrosinase activity in a mixed-type manner, with IC50 values ranging from 12.36 ± 1.24 to 86.67 ± 3.08 µM. To further elucidate the binding interactions, molecular docking simulations were performed, identifying key residues in the active site responsible for binding affinity. Furthermore, molecular dynamics (MD) simulations were conducted to assess the dynamic behavior, stability, and binding affinity of the most potent inhibitor, compound 6P. Quantitative Structure-Activity Relationship (QSAR) models were developed to correlate the structural features of the bis-pyrimidines with their inhibitory activity, providing insights into the structure-activity relationships (SAR) that govern their potency. The experimental and theoretical findings demonstrated excellent agreement. These findings pave the way for the development of novel bis-pyrimidine-based therapeutic agents for treating hyperpigmentation and related conditions.
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In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their in vitro α-glucosidase and α-amylase enzyme inhibition assays. The outcomes proved that this class of compounds exhibit considerable inhibitory activity against both enzymes. Among the target compounds, compounds 4p and 6p demonstrated the most potent dual inhibition with IC50 = 0.087 ± 0.01 µM for α-glucosidase; 0.189 ± 0.02 µM for α-amylase and IC50 = 0.095 ± 0.03 µM for α-glucosidase; 0.214 ± 0.03 µM for α-amylase, respectively as compared to the standard rutin (IC50 = 0.192 ± 0.02 µM for α-glucosidase and 0.224 ± 0.02 µM for α-amylase). Remarkably, the enzyme inhibition results indicate that test compounds have stronger inhibitory effect on the target enzymes than the positive control, with a significantly lower IC50 value. Moreover, these series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 0.087 ± 0.01 µM to 1.952 ± 0.26 µM. Furthermore, molecular docking studies were performed to affirm the binding interactions of this scaffold to the active sites of α-glucosidase and α-amylase enzymes. The quantitative structure-activity relationship (QSAR) investigations showed a strong association between 1p-15p structures and their inhibitory actions (IC50) with a correlation value (R2) of 0.999916. Finally, molecular dynamic (MD) simulations were carried out to assess the dynamic behavior, stability of the protein-ligand complex, and binding affinity of the most active inhibitor 4p. The experimental and theoretical results therefore exposed a very good compatibility. Additionally, the drug-likeness assay revealed that some compounds exhibit a linear association with Lipinski's rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets.Communicated by Ramaswamy H. Sarma.
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Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Simulação de Acoplamento Molecular , alfa-Glucosidases/química , Relação Estrutura-Atividade , alfa-Amilases , Estrutura MolecularRESUMO
Diabetes, also known as diabetes mellitus (DM), is a metabolic disorder characterized by an abnormal rise in blood sugar (glucose) levels brought on by a complete or partial lack of insulin secretion along with corresponding changes in the metabolism of lipids, proteins, and carbohydrates. It has been reported that medicinal plants play a pivotal role in the treatment of various ailments such as diabetes mellitus, dyslipidemia, and hypertension. The current study involved exploring the acute toxicity and in vivo antidiabetic activity of berberine (WA1), palmatine (WA2), and 8-trichloromethyl dihydroberberine (WA3) previously isolated from Berberis glaucocarpa Stapf using a streptozotocin (STZ)-induced diabetic rat model. Body weight and blood glucose level were assessed on a day interval for 4 weeks. Biochemical parameters, antioxidant enzymes, and oxidative stress markers were also determined. In an acute toxicity profile, the WA1, WA2, and WA3 were determined to be nontoxic up to 500 mg/kg (b.w). After the second and third weeks of treatment (14 and 21 days), the blood glucose levels in the WA1-, WA2-, and WA3-treated groups were significantly lower than those in the diabetic control group (476.81 ± 8.65 mg/dL, n = 8, P < 0.001). On the 21st day, there was a decrease in the blood glucose level and the results obtained were 176.33 ± 4.69, 197.21 ± 4.80, and 161.99 ± 4.75 mg/dL (n = 8, P < 0.001) for WA1, WA2, and WA3 at 12 mg/kg, respectively, as opposed to the diabetic control group (482.87 ± 7.11 mg/dL, n = 8, P < 0.001). Upon comparison with the diabetic group at the end of the study (28 days), a substantial drop in the glucose level of WA3 at 12 mg/kg (110.56 ± 4.11 mg/dL, n = 8, P < 0.001) was observed that was almost near the values of the normal control group. The treated groups (WA1, WA2, and WA3) treated with the samples displayed a significant decline in the levels of HbA1c. Treatment of the samples dramatically lowered the lipid level profile. In groups treated with samples, plasma levels of triglycerides, total cholesterol, and LDL were significantly lowered [F (5, 42) = 100.6, n = 8, P < 0.001]; these levels were also significantly decreased [F (5, 42) = 129.6 and 91.17, n = 8, P < 0.001]. In contrast to the diabetes group, all treated groups had significantly higher HDL levels [F (5, 42) = 15.46, n = 8, P < 0.001]. As a result, hypolipidemic activity was anticipated in the samples. In addition to that, the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was considerably elevated in the groups treated with the sample compared to the diabetic control group (n = 8, P < 0.001).
RESUMO
Terpyridine-based metal complexes have emerged as versatile and indispensable building blocks in the realm of modern chemistry, offering a plethora of applications spanning from materials science to catalysis and beyond. This comprehensive review article delves into the multifaceted world of terpyridine complexes, presenting an overview of their synthesis, structural diversity, and coordination chemistry principles. Focusing on their diverse functionalities, we explore their pivotal roles in catalysis, supramolecular chemistry, luminescent materials, and nanoscience. Furthermore, we highlight the burgeoning applications of terpyridine complexes in sustainable energy technologies, biomimetic systems, and medicinal chemistry, underscoring their remarkable adaptability to address pressing challenges in these fields. By elucidating the pivotal role of terpyridine complexes as versatile building blocks, this review provides valuable insights into their current state-of-the-art applications and future potential, thus inspiring continued innovation and exploration in this exciting area of research.