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Six known products (4-9) were prepared from reaction of adipoyl chloride with 1,2,3-trimethoxybenzene according to the literature. From (2,3,4-trimethoxyphenyl)(2-(2,3,4-trimethoxyphenyl)cyclopent-1-en-1-yl)methanone (4) of them, four new 1,2-disubstituted cyclopentane derivatives (10-13) with phenyl and benzyl units were synthesized by reactions such as hydrazonation, catalytic hydrogenation and bromination. The obtained compounds 4-13 were examined for their in vitro inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and α-glucosidase enzymes. All compounds 4-13 showed inhibition at nanomolar level with Ki values in the range of 45.53 ± 7.35-631.96 ± 18.88 nM for AChE, 84.30 ± 9.92-622.10 ± 35.14 nM for BChE, and 25.47 ± 4.46-48.87 ± 7.33 for α-Glu. In silico molecular docking studies of the potent compounds were performed in the active sites of AChE (PDB: 1E66), BChE (PDB: 1P0I), and α-glucosidase (PDB: 5ZCC) to compare the effect of bromine atom on the inhibition mechanism. The optimized molecular structures, HOMO-LUMO energies and molecular electrostatic potential maps for the compounds were calculated by using density functional theory with B3LYP/6-31 + G(d,p).
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In this work, a novel series of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a-n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole-N-phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.
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Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Simulación del Acoplamiento Molecular , Triazoles , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/síntesis química , Diseño de Fármacos , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Relación Estructura-Actividad , Saccharomyces cerevisiae/enzimología , CinéticaRESUMEN
In this study, (E)-4-{4-[(1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)methyl]phenoxy}phthalonitrile (4) and its phthalocyanine derivatives (5-8) were synthesized for the first time. Aggregation behaviors of the novel soluble phthalocyanines in organic solvents were investigated. In addition, the efficiency of 1O2 production of (5) and ZnPc (6) was investigated. The singlet oxygen quantum yields (ΦΔ) for 2HPc (5) and ZnPc (6) were found to be 0.58 and 0.83, respectively. Additionally, novel phthalocyanines (5-8) were investigated for their ability to inhibit enzymes. They exhibited a highly potent inhibition effect on human carbonic anhydrase I and II (hCA I and II) and α-glycosidase (α-Gly) enzymes. Ki values are in the range of 2.60 ± 9.87 to 11.53 ± 6.92 µM, 3.35 ± 0.53 to 15.47 ± 1.20 µM, and 28.60 ± 4.82 to 40.58 ± 7.37 nM, respectively. The calculations of the studied molecule at the B3LYP, HF, and M062X levels in the 6-31G basis sets were made using the Gaussian package program. Afterward, the interactions occurring in the docking calculation against a protein that is the crystal structure of hCA I (PDB ID: 2CAB), the crystal structure of hCA II (PDB ID: 5AML), and the crystal structure of α-Gly (PDB ID: 1R47), were examined. Following that, Protein-Ligand Interaction Profiler (PLIP) analysis was used to look at the interactions that occurred during the docking calculation in further detail.
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Mimosa pudica (MP) is an ornamental plant due to seismonastic movements that close leaves and fall petioles in response to touch, wind, light, heat, cold, and vibration. The seeds of MP secrete smart, biocompatible, and non-toxic mucilage that has captivated researchers due to its widespread use in various fields such as pharmaceuticals and biotechnology. The mucilage is responsive to pH, salt solutions, and solvents and acts as a binder in tablet formulations for targeted drug delivery. The mucilage is chemically modifiable via acetylation, succinylation, and graft polymerization. Chemically modified MP mucilage appeared supersorbent for heavy metal ion uptake. Nanoparticles synthesized using mucilage as a reducing and capping agent displayed significant antimicrobial and wound-healing potential. Crosslinking of mucilage using citric acid as a crosslinking agent offers a sustained release of drugs. The present review is aimed to discuss extraction optimization, structure, modification, and the stimuli-responsive nature of mucilage. The review article will cover the potential of mucilage as emulsifying, suspending, bio-adhesive, gelling, and thickening agent. The role of mucilage as a capping and reducing agent for nanoparticles will also be discussed.
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Mimosa , Mucílago de Planta , Semillas , Semillas/química , Mimosa/química , Mucílago de Planta/química , Nanopartículas/químicaRESUMEN
Probiotics are defined as "live microorganisms that provide health benefits to the host when administered in adequate amounts." Probiotics have beneficial effects on human health, including antibacterial activity against intestinal pathogens, regulation of blood cholesterol levels, reduction of colitis and inflammation incidence, regulation of the immune system, and prevention of colon cancer. In addition to probiotic bacteria, some phenolic compounds found in foods we consume (both food and beverages) have positive effects on human health. p-coumaric acid (p-CA) is one of the most abundant phenolic compounds in nature and human diet. The interactions between these two different food components (phenolics and probiotics), resulting in more beneficial combinations called synbiotics, are not well understood in terms of how they will affect the gut microbiota by promoting the probiotic properties and growth of probiotic bacteria. Thus, this study aimed to investigate synbiotic relationship between p-CA and Lactobacillus acidophilus LA-5 (LA-5), Lacticaseibacillus rhamnosus GG (LGG). Probiotic bacteria were grown in the presence of p-CA at different concentrations, and the effects of p-CA on probiotic properties, as well as its in vitro effects on AChE and BChE activities, were investigated. Additionally, Surface analysis was conducted using FTIR. The results showed that treatment with p-CA at different concentrations did not exhibit any inhibitory effect on the growth kinetics of LA-5 and LGG probiotic bacteria. Additionally, both probiotic bacteria demonstrated high levels of antibacterial properties. It showed that it increased the auto-aggregation of both probiotics. While p-CA increased co-aggregation of LA-5 and LGG against Escherichia coli, it decreased co-aggregation against Staphylococcus aureus. Probiotics grown with p-CA were more resistant to pepsin. While p-CA increased the resistance of LA-5 to bile salt, it decreased the resistance of LGG. The combinations of bacteria and p-CA efficiently suppressed AChE and BChE with inhibition (%) 11.04-68.43 and 13.20-65.72, respectively. Furthermore, surface analysis was conducted using FTIR to investigate the interaction of p-coumaric acid with LA-5 and LGG, and changes in cell components on the bacterial surface were analyzed. The results, recorded in range of 4000 -600 cm-1 with resolution of 4 cm-1, demonstrated that p-CA significantly affected only the phosphate/CH ratio for both bacteria. These results indicate the addition of p-CA to the probiotic growth may enhance the probiotic properties of bacteria.
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Ácidos Cumáricos , Lacticaseibacillus rhamnosus , Probióticos , Humanos , Lactobacillus acidophilus , Probióticos/farmacología , Antibacterianos/farmacologíaRESUMEN
Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.
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Cromonas , Diabetes Mellitus Tipo 2 , Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Simulación del Acoplamiento Molecular , Tiosemicarbazonas , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Cromonas/farmacología , Cromonas/síntesis química , Cromonas/química , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismo , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estructura Molecular , Humanos , Simulación de Dinámica Molecular , Simulación por Computador , Relación Dosis-Respuesta a DrogaRESUMEN
Many human cancers have been associated with the deregulation of the mesenchymal-epithelial transition factor tyrosine kinase (MET) receptor, a promising drug target for anticancer drug discovery. Herein, we report the discovery of a novel structure of potent chalcone-based derivatives type II c-Met inhibitors which are comparable to Foretinib (IC50 = 14 nM) as a potent reference drug. Based on our design strategy, we also expected an anti-tubulin activity for the compounds. However, the weak inhibitory effects on microtubules were confirmed by cell cycle analyses implicated that the observed cytotoxicity against HeLa cells probably was not derived from tubulin inhibition. Compounds 14q and 14k with IC50 values of 24 nM and 45 nM, respectively, demonstrated favorable inhibition of MET kinase activity, and desirable bonding interactions in the ligand-MET enzyme complex stability in molecular docking studies.
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In diabetes mellitus, amylase and glucosidase enzymes are the primary triggers. The main function of these enzymes is to break macromolecules into simple sugar units, which directly affect blood sugar levels by increasing blood permeability. To overcome this metabolic effect, there is a need for a potent and effective inhibitor capable of suppressing the enzymatic conversion of sugar macromolecules into their smaller units. Herein, we reported the discovery of a series of substituted triazolo[4,3-b][1,2,4]triazine derivatives as α-glucosidase and α-amylase inhibitors. All target compounds demonstrated significant inhibitory activities against α-glucosidase and α-amylase enzymes compared with acarbose as the positive control. The most potent compound 10k, 2-[(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)thio]-N-[4-(trifluoromethyl)phenyl]acetamide, demonstrated IC50 values of 31.87 and 24.64 nM against α-glucosidase and α-amylase enzymes, respectively. To study their mechanism of action, kinetic studies were also done, which determined the mode of inhibition of both enzymes. Molecular docking was used to confirm the binding interactions of the most active compounds.
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Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , Triazinas , alfa-Amilasas , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismo , Triazinas/farmacología , Triazinas/síntesis química , Triazinas/química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Humanos , Triazoles/farmacología , Triazoles/química , Triazoles/síntesis químicaRESUMEN
An extensive range of new biologically active morpholine based thiosemicarbazones derivatives 3a-r were synthesized, characterized by spectral techniques and evaluated as inhibitors of ENPP isozymes. Most of the novel thiosemicarbazones exhibit potent inhibition towards NPP1 and NPP3 isozymes. Compound 3â¯h was potent inhibitor of NPP1 with IC50 value of 0.55⯱â¯0.02. However, the most powerful inhibitor of NPP3 was 3e with an IC50 value of 0.24⯱â¯0.02. Furthermore, Lineweaver-Burk plot for compound 3â¯h against NPP1 and for compound 3e against NPP3 was devised through enzymes kinetics studies. Molecular docking and in silico studies was also done for analysis of interaction pattern of all newly synthesized compounds. The results were further validated by molecular dynamic (MD) simulation where the stability of conformational transformation of the best protein-ligand complex (3e) were justified on the basis of RMSD and RMSF analysis.
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Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Morfolinas , Hidrolasas Diéster Fosfóricas , Pirofosfatasas , Tiosemicarbazonas , Morfolinas/química , Morfolinas/farmacología , Morfolinas/síntesis química , Hidrolasas Diéster Fosfóricas/química , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/antagonistas & inhibidores , Pirofosfatasas/química , Pirofosfatasas/metabolismo , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/síntesis química , Humanos , Cinética , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Simulación por Computador , Relación Estructura-Actividad , LigandosRESUMEN
Inhibition of α-glucosidase and α-amylase is an important target for treatment of type 2 diabetes. In this work, a novel series of pyrano[2,3-b]chromene derivatives 5a-m was designed based on potent α-glucosidase and α-amylase inhibitors and synthesized by simple chemical reactions. These compounds were evaluated against the latter enzymes. Most of the title compounds exhibited high inhibitory activity against α-glucosidase and α-amylase in comparison to standard inhibitor (acarbose). Representatively, the most potent compound, 4-methoxy derivative 5d, was 30.4 fold more potent than acarbose against α-glucosidase and 6.1 fold more potent than this drug against α-amylase. In silico molecular modeling demonstrated that compound 5d attached to the active sites of α-glucosidase and α-amylase with a favorable binding energies and established interactions with important amino acids. Dynamics of compound 5d also showed that this compound formed a stable complex with the α-glucosidase active site. In silicodrug-likeness as well as ADMET prediction of this compound was also performed and satisfactory results were obtained.
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Diabetes Mellitus Tipo 2 , Inhibidores de Glicósido Hidrolasas , Humanos , Inhibidores de Glicósido Hidrolasas/química , Acarbosa , Diabetes Mellitus Tipo 2/tratamiento farmacológico , alfa-Glucosidasas/metabolismo , Simulación del Acoplamiento Molecular , Cromonas/farmacología , Cromonas/química , alfa-Amilasas , Relación Estructura-ActividadRESUMEN
The paper is focused on biological activity and theoretical study of the structure and properties of a new azo derivative of ß-diketones and its complexes with some metals. The aim of our work was to study the structure and properties of the newly synthesized compound as well as to theoretically determine the possibility of complex formation with the Cu(II) or Co(II) ions. A compound with the same substituents R1=R2=CH3 was chosen for the study. A synthesized azo compound based on 4-amino antipyrine and its complexes with Cu(II), Co(II) in solution and solid phase is reported. The structures of these compounds have been testified by X-ray, IR and NMR spectroscopy. The combined experimental and theoretical approach was used. To study the structure and properties of the synthesized compound, as well as its possible complex formation with the Cu(II), quantum-chemical calculations were carried out the 6-31G basis set and the electron density functional theory (DFT) method. These 3-(1-phenyl-2,3-dimethyl-pyrazolone-5) azopentadione-2,4 (PDPA) with Cu(II) and Co(II) complexes had effective inhibition against butyrylcholinesterase and acetylcholinesterase. IC50 values were found as 19.03, 3.64â µM for AChE and 28.47, 8.01â µM for BChE, respectively. Cholinesterase inhibitors work to slow down the acetylcholine's deterioration.
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Butirilcolinesterasa , Complejos de Coordinación , Acetilcolinesterasa/química , Butirilcolinesterasa/química , Complejos de Coordinación/química , Metales/química , Modelos Teóricos , Simulación del Acoplamiento Molecular , Cobre/química , Cobalto/químicaRESUMEN
A synthesized azo compound based on 4-amino antipyrine and its complexes with Ni(II) in solution and solid phase is reported. The structures of these compounds have been testified by IR and NMR spectroscopy. The combined experimental and theoretical approach was used. To study the structure and properties of the synthesized compound, as well as its possible complex formation with the Ni(II), ab initio quantum-chemical calculations were carried out using the Hartree-Fock (HF) method with the 6-31 G basis set and the electron density functional theory (DFT) method with hybrid three-parameter potential B3LYP and extended basis set 6-311++G(d,p) taking into account polarization and diffuse functions for all atoms. The geometric, energy, and electronic parameters were calculated and analyzed. The HOMO-LUMO energy gap has been calculated to determine chemical activity. Both complexes had effective inhibition against butyrylcholinesterase and acetylcholinesterase. IC50 values were found as 19.43 and 27.08⯵M for AChE, 2.37 and 7.40⯵M for BChE, respectively. For the anticancer outcome, high doses of compound E1 inhibited viability by about 40-45%, while this rate was around 65-70% for compound E2 at the same doses. Anticholinesterase and anticancer potential of compounds E1 and E2 also evaluated by in silico techniques. Both compounds show strong binding to VEGFR1, with E2 exhibiting superior inhibitory activity in hAChE and hBChE through shorter and stronger interactions. MD simulations suggest that E2 forms more stable complexes with hAChE and hBChE compared to E1, making it a promising candidate for further exploration in anticancer and anticholinesterase therapies.Communicated by Ramaswamy H. Sarma.
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In this study, we researched the reactions of 5-(5-bromofuran-2-yl)-4-methyl-1,2,4-triazole-3-thiol and 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols with some halogen-containing compounds, a number of new compounds were synthesized (1.1-1.5 and 2.1-2.8). These compounds showed excellent to good inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. For obtaining the effects of these compounds on AChE and BChE enzymes were determined spectrophotometrically according to Ellman. IC50 values of these enzymes were ranging between 1.63 and 17.68 nM for AChE and 8.71 and 84.02 nM for BChE. After, prostate cancer is the second leading cause of cancer-related mortality for men over the age of 65 in developed countries. Current treatment options remain limited in the treatment of advanced-stage prostate cancer leading to biochemical recurrence in almost 40% of the patients. Therefore, there is an urgent need for development of novel therapeutic tools for treatment of prostate cancer patients. In this study, we aimed at analyzing the potential of all compounds against prostate cancer cells. We found that, of the tested compounds, 2.1, 2.2 and 2.3 showed significant cytotoxic activities against PC3 prostate cancer cells, although their effect on the viability of normal prostate cells was limited. These findings suggest their selective targeting potential for prostate cancer cells and offer them as candidate therapeutic agents against prostate cancer. The inhibitory activities of some chemical compounds, such as (1.1-1.5 and 2.1-2.8) were assessed by performing the molecular docking study in the presence of AChE, BChE and prostate cancer protein. MM/GBSA methods are calculated binding free energy. Finally, ADME/T analysis was performed to examine the drug properties of the 13 studied molecules.Communicated by Ramaswamy H. Sarma.
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Butirilcolinesterasa , Neoplasias de la Próstata , Triazoles , Humanos , Masculino , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Simulación del Acoplamiento Molecular , Diseño de Fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Relación Estructura-Actividad , Estructura MolecularRESUMEN
N-substitued anthranilic acid derivatives are commonly found in the structure of many biologically active molecules. In this study, new members of hydrazones derived from anthranilic acid (1-15) were synthesized and investigated their effect on some metabolic enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). Results indicated that all the molecules exhibited potent inhibitory effects against all targets as compared to the standard inhibitors, revealed by IC50 values. Ki values of compounds for AChE, BChE, and α-Gly enzymes were obtained in the ranges 66.36 ± 8.30-153.82 ± 13.41, 52.68 ± 6.38-113.86, and 2.13 ± 0.25-2.84 nM, respectively. The molecular docking study was performed for the most active compounds to the determination of ligand-enzyme interactions. Binding affinities of the most active compound were found at the range of -9.70 to -9.00 kcal/mol for AChE, -11.60 to -10.60 kcal/mol for BChE, and -10.30 to -9.30 kcal/mol for α-Gly. Molecular docking simulations showed that the novel compounds had preferential interaction with AChE, BChE, and α-Gly. Drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyzes of all synthesized compounds (1-15) were estimated and their toxic properties were evaluated as well as their therapeutic properties. Moreover, molecular dynamics simulations were carried out to understand the accuracy of the most potent derivatives of docking studies.
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Acetilcolinesterasa , Butirilcolinesterasa , ortoaminobenzoatos , Butirilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Simulación del Acoplamiento Molecular , Hidrazonas/farmacología , Relación Estructura-Actividad , Glicósido Hidrolasas/metabolismo , Estructura MolecularRESUMEN
This work includes the synthesis of a new series of palladium-based complexes containing both morpholine and N-heterocyclic carbene (NHC) ligands. The new complexes were characterized using NMR (1 H and 13 C), FTIR spectroscopic, and elemental analysis techniques. The crystal structure of complex 1b was obtained by utilizing the single-crystal X-ray diffraction method. X-ray studies show that the coordination environment of palladium atom is completed by the carbene carbon atom of the NHC ligand, the nitrogen atom of the morpholine ring, and a pair of bromide ligand, resulting in the formation of slightly distorted square planar geometry. All complexes were determined for some metabolic enzyme activities. Results indicated that all the synthetic complexes exhibited powerful inhibitory actions against all aims as compared to the control molecules. Ki values of new morpholine-liganded complexes bearing 4-hydroxyphenylethyl group 1a-e for hCA I, hCA II, AChE, BChE, and α-glycosidase enzymes were obtained in the ranges 0.93-2.14, 1.01-2.03, 4.58-10.27, 7.02-13.75, and 73.86-102.65 µM, respectively. Designing of reported complexes is impacted by molecular docking study, and interaction with the current enzymes also proclaimed that compounds 1e (-12.25 kcal/mol for AChE and -11.63 kcal/mol for BChE), 1c (-10.77 kcal/mol and -9.26 kcal/mol for α-Gly and hCA II, respectively), and 1a (-8.31 kcal/mol for hCA I) are showing binding affinity and interaction from the synthesized five novel complexes.
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Metano/análogos & derivados , Morfolinas , Paladio , Estructura Molecular , Simulación del Acoplamiento Molecular , Paladio/química , Ligandos , Morfolinas/farmacologíaRESUMEN
Diabetes mellitus (DM) has prevailed as a chronic health condition and has become a serious global health issue due to its numerous consequences and high prevalence. We have synthesized a series of hydrazone derivatives and tested their antidiabetic potential by inhibiting the essential carbohydrate catabolic enzyme, "α-glucosidase." Several approaches including fourier transform infrared, 1 H NMR, and 13 C NMR were utilized to confirm the structures of all the synthesized derivatives. In vitro analysis of compounds 3a-3p displayed more effective inhibitory activities against α-glucosidase with IC50 in a range of 2.80-29.66 µM as compared with the commercially available inhibitor, acarbose (IC50 = 873.34 ± 1.67 M). Compound 3h showed the highest inhibitory potential with an IC50 value of 2.80 ± 0.03 µM, followed by 3i (IC50 = 4.13 ± 0.06 µM), 3f (IC50 = 5.18 ± 0.10 µM), 3c (IC50 = 5.42 ± 0.11 µM), 3g (IC50 = 6.17 ± 0.15 µM), 3d (IC50 = 6.76 ± 0.20 µM), 3a (IC50 = 9.59 ± 0.14 µM), and 3n (IC50 = 10.01 ± 0.42 µM). Kinetics analysis of the most potent compound 3h revealed a concentration-dependent form of inhibition by 3h with Ki value = 4.76 ± 0.0068 µM. Additionally, an in silico docking approach was applied to predict the binding patterns of all the compounds, which indicates that the hydrazide and the naphthalene-ol groups play a vital role in the binding of the compounds with the essential residues (i.e., Glu277 and Gln279) of the α-glucosidase enzyme.
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Diabetes Mellitus , Inhibidores de Glicósido Hidrolasas , Humanos , Estructura Molecular , Relación Estructura-Actividad , Hidrazonas/farmacología , Hidrazonas/química , alfa-Glucosidasas/metabolismo , Simulación del Acoplamiento Molecular , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
In this work, synthesis and evaluation of pyrazino[1,2-a]indole-1,4-dione-indole-2-phenylacetamides 6 a-k as new synthetic anti-diabetes agents were presented. These compounds were synthesized by a four-component Ugi reaction without metal catalyst. All synthesized compounds were evaluated against α-glucosidase and α-amylase as two important targets in the treatment of diabetes. Approximately, all new compounds 6 a-k were more potent than positive control acarbose against these studied enzymes. The obtained potent compounds against the target enzymes were docked in the active site of the related enzyme. Docking study showed that our new potent compounds as well interacted with key residues of the target enzyme.
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Bencenoacetamidas , Inhibidores de Glicósido Hidrolasas , alfa-Amilasas/metabolismo , alfa-Glucosidasas/metabolismo , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/química , Indoles/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Acetamidas/química , Acetamidas/metabolismoRESUMEN
Oxazolidinones are used as various potent antibiotics, in organisms it acts as a protein synthesis inhibitor, focusing on an initial stage that encompasses the tRNA binding process. Novel intramolecular aza-Michael reactions devoid of metal catalysts have been introduced in an oxazolidone synthesis pathway, different from α,ß-unsaturated ketones. Oxazolidinone derivatives were tested against acetylcholinesterase (AChE), carbonic anhydrase I and II (hCA I and hCA II) enzymes. All the synthesized compounds had potent inhibition effects with Ki values in the range of 13.57 ± 0.98 - 53.60 ± 6.81 µM against hCA I and 9.96 ± 1.02 - 46.35 ± 3.83 µM against hCA II in comparison to the acetazolamide (AZA) (Ki = 50.46 ± 6.17 µM for hCA I) and for hCA II (Ki = 41.31 ± 5.05 µM). Also, most of the compounds demonstrated potent inhibition ability towards AChE enzyme with Ki values 78.67-231.75 nM and compared to tacrine (TAC) as standard clinical inhibitor (Ki = 142.48 nM). Furthermore, ADMET analysis and molecular docking were calculated using the AChE, hCA I and hCA II enzyme proteins to correlate the data with the experimental data. In this work, recent applications of a stereoselective aza-Michael reaction as an efficient tool for of nitrogen-containing heterocyclic scaffolds and their useful to pharmacology analogs are reviewed and summarized.Communicated by Ramaswamy H. Sarma.
RESUMEN
In this study, new Schiff base compounds (SB-F-OH, SB-Cl-OH and SB-Br-OH) were derived from chalcone-derived amine compounds containing halogen groups and 4-hydroxybenzaldehyde. Also, their phthalonitrile compounds (SB-F-CN, SB-Cl-CN and SB-Br-CN) have been synthesized. The structures of these compounds were elucidated by NMR, FT-IR and Mass spectroscopic methods. The quantum chemical parameters were calculated at B3LYP/6-31++g(d,p), HF/6-31++g(d,p) and M062X/6-31++g(d,p) levels. As the biological application of the synthesized compounds, (i) their inhibition properties of the synthesized compounds on Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) metabolic enzymes were investigated, and their potential anticancer activities against neuroblastoma (NB; SH-SY5Y) and healthy fibroblast (NIH-3T3) cell lines were determined by in vitro assays. All compounds showed inhibition at nanomolar level with the Ki values in the range of 97.86 ± 30.51-516.82 ± 31.42 nM for AChE, 33.21 ± 4.45-78.50 ± 8.91 nM for BChE, respectively. It has been determined that all tested compounds have a remarkable cytotoxic effect against SH-SY5Y, and IC50 values were significantly lower than NIH-3T3 cells. The lowest IC50 value was observed in SB-Cl-OH (7.48 ± 0.86 µM) and SB-Cl-CN (7.31 ± 0.69 µM). The molecular docking of the molecules was also investigated using crystal structure of AChE enzyme protein (PDB ID: 4M0E), crystal structure of BChE protein (PDB ID: 6R6V) and SH-SY5Y cancer protein (PDB ID: 2F3F, 3PBL and 5WIV). The ADME properties of the compounds were investigated. MM/GBSA method is calculated binding free energy. Afterwards, ADME/T analysis was performed to examine the some properties of the molecules.Communicated by Ramaswamy H. Sarma.
RESUMEN
Two novel quinoline-anthracene conjugates comprising styrylquinoline and anthracene moieties linked by triazole bridges were designed and synthesized in good yields. These molecules were determined for some metabolic enzymes activities. Results indicated that the synthetic molecules exhibited powerful inhibitory actions against all aims as compared to the control molecules. Ki values of novel compound QA-1 for hCA I, hCA II, AChE, and α-glycosidase enzymes were obtained of 20.18 ± 2.46 µM, 14.63 ± 1.14 µM, 71.48 ± 7.76 nM, 401.35 ± 36.84 nM, respectively. Both compounds showed promising candidate complexes for drug development with considerable in vitro different enzymes inhibitory activities. The binding conformations patterns and interaction of QA-1 and QA-2 compounds with α-glucosidase, acetycholinesterase, carbonic anhydrase-I and carbonic anhydrase-II enzymes were investigated through molecular docking profiles. The docking outputs are consistent with the Ki and IC50 values of novel compounds. Three dimensional geometries and electronic properties of the title compounds were obtained by the applicational computational approach at B3LYP/6-31++G(d,p) level of theory.Communicated by Ramaswamy H. Sarma.