RESUMEN
The current study involves the synthesis of Schiff bases based on 1,2,4-triazoles skeleton and assessing their α-amylase and α-glucosidase profile. Furthermore, the precise structures of the synthesized derivatives were elucidated using various spectroscopic methods such as 1H-NMR, 13C-NMR and HREI-MS. Using glimepiride as the reference standard, the in vitro α-glucosidase and α-amylase inhibitory activities of the synthesized compounds were evaluated in order to determine their potential anti-diabetic properties. All analogues showed varied range of inhibitory activity having IC50 values ranging from 17.09 ± 0.72 to 45.34 ± 0.03⯵M (α-amylase) and 16.35 ± 0.42 to 42.31 ± 0.09⯵M (α-glucosidase), respectively. Specifically, the compounds 1, 7 and 8 were found to be significantly active with IC50 values of 17.09 ± 0.72, 19.73 ± 0.42, and 23.01 ± 0.04⯵M (against α-amylase) and 16.35 ± 0.42, 18.55 ± 0.26, and 20.07 ± 0.02⯵M (against α-glucosidase) respectively. The obtained results were compared with the Glimepiride reference drug having IC50 values of 13.02 ± 0.11⯵M (for α-glucosidase) and 15.04 ± 0.02⯵M (for α-amylase), respectively. The structure-activity relationship (SAR) studies were conducted based on differences in substituent patterns at varying position of aryl rings A and B may cause to alter the inhibitory activities of both α-amylase and α-glucosidase enzymes. Additionally, the molecular docking study was carried out to explore the binding interactions possessed by most active analogues with the active sites of targeted α-amylase and α-glucosidase enzymes.
RESUMEN
A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC50 = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.
RESUMEN
A series of 3-substituted and 3,5-disubstituted rhodanine-based derivatives were synthesized from 3-aminorhodanine and examined for α-amylase inhibitory, DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities in vitro. These derivatives displayed significant α-amylase inhibitory potential with IC50 values of 11.01-56.04 µM in comparison to standard acarbose (IC50 = 9.08 ± 0.07 µM). Especially, compounds 7 (IC50 = 11.01 ± 0.07 µM) and 8 (IC50 = 12.01 ± 0.07 µM) showed highest α-amylase inhibitory activities among the whole series. In addition to α-amylase inhibitory activity, all compounds also demonstrated significant scavenging activities against DPPH and ABTS radicals, with IC50 values ranging from 12.24 to 57.33 and 13.29-59.09 µM, respectively, as compared to the standard ascorbic acid (IC50 = 15.08 ± 0.03 µM for DPPH; IC50 = 16.09 ± 0.17 µM for ABTS). These findings reveal that the nature and position of the substituents on the phenyl ring(s) are crucial for variation in the activities. The structure-activity relationship (SAR) revealed that the compounds bearing an electron-withdrawing group (EWG) at para substitution possessed the highest activity. In kinetic studies, only the km value was changed, with no observed changes in Vmax, indicating a competitive inhibition. Molecular docking studies revealed important interactions between compounds and the α-amylase active pocket. Further advanced research needs to perform on the identified compounds in order to obtain potential antidiabetic agents.
RESUMEN
Background: Unsymmetrical thioureas 1-20 were synthesized and then characterized by various spectroscopy techniques such as UV, IR, fast atom bombardment (FAB)-MS, high-resolution FAB-MS, 1H-NMR and 13C-NMR. Methods: Synthetic compounds 1-20 were tested for their ability for antioxidant, lipoxygenase and xanthine oxidase activities. Results: Compounds 1, 2, 9, 12 and 15 exhibited strong antioxidant potential, whereas compounds 1-3, 9, 12, 15 and 19 showed good to moderate lipoxygenase activity. Ten compounds demonstrated moderate xanthine oxidase inhibition. Conclusion: Compound 15 displayed the highest potency among the series, exhibiting good antioxidant, lipoxygenase and xanthine oxidase activities. Theoretical calculations using density functional theory and molecular docking studies supported the experimental findings, indicating the potential of the synthesized compounds as potent antioxidants, lipoxygenases and xanthine oxidase agents.
Asunto(s)
Antioxidantes , Lipooxigenasa , Antioxidantes/química , Simulación del Acoplamiento Molecular , Xantina Oxidasa/química , Xantina Oxidasa/metabolismo , Inhibidores Enzimáticos/química , Tiourea/farmacología , Tiourea/química , Relación Estructura-ActividadRESUMEN
A rare but lethal central nervous system disease known as granulomatous amoebic encephalitis (GAE) and potentially blinding Acanthamoeba keratitis are diseases caused by free-living Acanthamoeba. Currently, no therapeutic agent can completely eradicate or prevent GAE. Synthetic compounds are a likely source of bioactive compounds for developing new drugs. This study synthesized seventeen 1,4-benzothiazine derivatives (I -XVII) by a base-catalyzed one-pot reaction of 2-amino thiophenol with substituted bromo acetophenones. Different spectroscopic techniques, such as EI-MS, 1H-, and 13C NMR (only for the new compounds), were used for the structural characterization and conformation of compounds. These compounds were assessed for the first time against Acanthamoeba castellanii. All compounds showed anti-amoebic potential in vitro against A. castellanii, reducing its ability to encyst and excyst at 100 µM. Compounds IX, X, and XVI showed the most potent activities among all derivatives and significantly reduced the viability to 5.3 × 104 (p < 0.0003), 2 × 105 (p < 0.006), and 2.4 × 105 (p < 0.002) cells/mL, respectively. The cytotoxicity profile revealed that these molecules showed lower to moderate cytotoxicity, i.e., 36 %, 2 %, and 21 %, respectively, against human keratinocytes in vitro. These results indicate that 1,4-benzothiazines showed potent in vitro activity against trophozoites and cysts of A. castellanii. Hence, these 1,4-benzothiazine derivatives should be considered to develop new potential therapeutic agents against Acanthamoeba infections.
RESUMEN
Existing drugs that are being used to treat type-2 diabetes mellitus are associated with several side effects; thus, exploring potential drug candidates is still an utter need these days. Hybrids of indenoquinoxaline and hydrazide have never been explored as antidiabetic agents. In this study, a series of new indenoquinoxaline-phenylacrylohydrazide hybrids (1-30) were synthesized, structurally characterized, and evaluated for α-amylase and α-glucosidase inhibitory activities, as well as for their antioxidant properties. All scaffolds exhibited varying degrees of inhibitory activity against both enzymes, with IC50 values ranging from 2.34 to 61.12 µM for α-amylase and 0.42 to 54.72 µM for α-glucosidase. Particularly, compounds 10, 16, 17, 18, 24, and 25 demonstrated the highest efficacy in inhibiting α-amylase, while compounds 6, 7, 8, 10, 12, 14, 13, 16, 17, 18, 24, and 25 were the most effective α-glucosidase inhibitors, compared to standard acarbose. Moreover, most of these compounds displayed substantial antioxidant potential compared to standard butylated hydroxytoluene (BHT). Kinetics studies revealed competitive inhibition modes by compounds. Furthermore, a comprehensive in silico study and toxicity prediction were also conducted, further validating these analogs as potential drug candidates. The structured compounds demonstrated enhanced profiles, underscoring their potential as primary candidates in drug discovery.
Asunto(s)
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , alfa-Glucosidasas/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/uso terapéutico , alfa-Amilasas/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Helicobacter pylori causes severe stomach disorders and the use of enzyme inhibitors for treatment is one of the possible therapies. The great biological potential of imine analogs as urease inhibitors has been the focus of researchers in past years. In this regard, we have synthesized twenty-one derivatives of dichlorophenyl hydrazide. These compounds were characterized by different spectroscopic techniques i.e. NMR and HREI-MS. Compounds 2 and 10 were found to be the most active in the series. Structure-activity relationship has been established for all compounds based on different substituents attached to the phenyl ring that play a vital role in enzyme inhibition. From the structure-activity relationship, it has been observed that these analogs showed excellent potential for urease and can be an alternate therapy in the future. The molecular docking study was performed to further explore the binding interactions of synthesized analogs with enzyme active sites.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Hidrazinas , Ureasa , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Hidrazinas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Estructura MolecularRESUMEN
Geographic atrophy (GA) is a progressive form of age-related macular degeneration characterized by the degeneration of retinal pigment epithelial cells and photoreceptor death. The dysregulation of the complement cascade has been implicated in GA progression. This review provides a comprehensive overview of the pathophysiology of age-related macular degeneration and GA, discusses current therapeutic options, and focuses on the recent breakthrough drug, pegcetacoplan (SYFOVRE). Pegcetacoplan is a complement inhibitor that selectively targets the C3 complement protein, effectively modulating complement activation. Clinical trials, including the OAKS and DERBY studies, have demonstrated the efficacy of SYFOVRE in reducing the growth of GA lesions compared to placebo. The FDA approval of SYFOVRE as the first and only definitive therapy for GA marks a significant milestone in the management of this debilitating condition. The review also explores potential future treatment strategies, including immune-modulating agents and ocular gene therapy. While SYFOVRE offers new hope for GA patients, further research is needed to evaluate its long-term benefits, safety profile, and optimal treatment regimens.
RESUMEN
Background: Diabetes mellitus is a significant health disorder; therefore, researchers should focus on discovering new drug candidates. Methods: A series of indole-pyridine carbonitrile derivatives, 1-34, were synthesized through a one-pot multicomponent reaction and evaluated for antidiabetic and antioxidant potential. Results: In this library, 12 derivatives - 1, 2, 4, 5, 7, 8, 10-12, 14, 15 and 31 - exhibited potent inhibitory activities against α-glucosidase and α-amylase enzymes, in comparison to acarbose (IC50 = 14.50 ± 0.11 µM). Furthermore, kinetics, absorption, distribution, metabolism, excretion and toxicity and molecular docking studies were used to interpret the type of inhibition, binding energies and interactions of ligands with target enzymes. Conclusion: These results indicate that the compounds may be promising hits for controlling diabetes mellitus and its related complications.
Asunto(s)
Diabetes Mellitus , Inhibidores de Glicósido Hidrolasas , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Glicósido Hidrolasas/química , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/química , Piridinas/química , Indoles/farmacología , Indoles/uso terapéutico , Relación Estructura-Actividad , Estructura MolecularRESUMEN
Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50 = 1.19-18.92 µM) compared with standard thiourea (IC50 = 19.53 ± 0.032 µM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.
Asunto(s)
Inhibidores Enzimáticos , Quinolinas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Ureasa/química , Ureasa/metabolismo , Cinética , Simulación del Acoplamiento Molecular , Tiourea/química , Tiourea/farmacología , Aminoquinolinas , Quinolinas/farmacología , Relación Estructura-Actividad , Estructura MolecularRESUMEN
A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α-glucosidase and α-amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC50 = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for α-amylase, noncompetitive-type inhibition for α-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.
Asunto(s)
Enfermedad de Alzheimer , Diabetes Mellitus , Humanos , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , alfa-Glucosidasas/metabolismo , Acarbosa , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Oxadiazoles/farmacología , alfa-AmilasasRESUMEN
Background: Diabetes mellitus (DM) is a chronic disorder, considered to be a major global health challenge in the 21st century. α-Glucosidase enzyme is a well-known drug target to treat Type II DM. Methods: A new library of biphenyl-substituted triazines was synthesized and confirmed by various spectroscopic techniques. Results: All compounds showed potent α-glucosidase inhibitory activity, with IC50 values ranging from 35.35 ± 0.34 to 564.41 ± 0.91 µM, as the standard acarbose, IC50 value of 750.7 ± 0.13 µM. Our in silico study has predicted key interactions with the enzyme's active site. Drug-likeness and absorption, distribution, metabolism, excretion and toxicity were also studied. Conclusion: This study has identified a range of potential hits against the α-glucosidase enzyme that may serve as antidiabetic agents after further investigations.
Asunto(s)
Inhibidores de Glicósido Hidrolasas , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/química , alfa-Glucosidasas/metabolismo , Hipoglucemiantes/química , Cinética , Triazinas/farmacología , Triazinas/química , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Estructura MolecularRESUMEN
Background: Researchers seeking new drug candidates to treat diabetes mellitus have been exploring bioactive molecules found in nature, particularly tetrahydropyridines (THPs). Methods: A library of THPs (1-31) were synthesized via a one-pot multicomponent reaction and investigated for their inhibition potential against α-glucosidase and α-amylase enzymes. Results: A nitrophenyl-substituted compound 5 with IC50 values of 0.15 ± 0.01 and 1.10 ± 0.04 µM, and a Km value of 1.30 mg/ml was identified as the most significant α-glucosidase and α-amylase inhibitor, respectively. Kinetic studies revealed the competitive mode of inhibition, and docking studies revealed that compound 5 binds to the enzyme by establishing hydrophobic and hydrophilic interactions and a salt bridge interaction with His279. Conclusion: These molecules may be a potential drug candidate for diabetes in the future.
Asunto(s)
Diabetes Mellitus , Inhibidores de Glicósido Hidrolasas , Humanos , alfa-Amilasas/antagonistas & inhibidores , alfa-Glucosidasas/metabolismo , Inhibidores de Glicósido Hidrolasas/química , Cinética , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
Twenty-one analogs were synthesized based on benzimidazole, incorporating a substituted benzaldehyde moiety (1-21). These were then screened for their acetylcholinesterase and butyrylcholinesterase inhibition profiles. All the derivatives except 13, 14, and 20 showed various inhibitory potentials, ranging from IC50 values of 0.050 ± 0.001 µM to 25.30 ± 0.40 µM against acetylcholinesterase, and 0.080 ± 0.001 µM to 25.80 ± 0.40 µM against butyrylcholinesterase, when compared with the standard drug donepezil (0.016 ± 0.12 µM and 0.30 ± 0.010 µM, against acetylcholinesterase and butyrylcholinesterase, respectively). Compound 3 in both cases was found to be the most potent compound due to the presence of chloro groups at the 3 and 4 positions of the phenyl ring. A structure-activity relationship study was performed for all the analogs except 13, 14, and 20, further, molecular dynamics simulations were performed for the top two compounds as well as the reference compound in a complex with acetylcholinesterase and butyrylcholinesterase. The molecular dynamics simulation analysis revealed that compound 3 formed the most stable complex with both acetylcholinesterase and butyrylcholinesterase, followed by compound 10. As compared to the standard inhibitor donepezil both compounds revealed greater stabilities and higher binding affinities for both acetylcholinesterase and butyrylcholinesterase.
RESUMEN
The clinical significance of benzimidazole-containing drugs has increased in the current study, making them more effective scaffolds. These moieties have attracted strong research interest due to their diverse biological features. To examine their various biological significances, several research synthetic methodologies have recently been established for the synthesis of benzimidazole analogs. The present study aimed to efficiently and quickly synthesize a new series of benzimidazole analogs. Numerous spectroscopic techniques, including 1H-NMR, 13C-NMR, and HREI-MS, were used to confirm the synthesized compounds. To explore the inhibitory activity of the analogs against α-amylase and α-glucosidase, all derivatives (1-17) were assessed for their biological potential. Compared to the reference drug acarbose (IC50 = 8.24 ± 0.08 µM), almost all the derivatives showed promising activity. Among the tested series, analog 2 (IC50 = 1.10 ± 0.10 & 2.10 ± 0.10 µM, respectively) displayed better inhibitory activity. Following a thorough examination of the various substitution effects on the inhibitory capacity of α-amylase and α-glucosidase, the structure-activity relationship (SAR) was determined. We looked at the potential mechanism of how active substances interact with the catalytic cavity of the targeted enzymes in response to the experimental results of the anti-glucosidase and anti-amylase. Molecular docking provided us with information on the interactions that the active substances had with the various amino acid residues of the targeted enzymes for this purpose.
RESUMEN
Diabetes is also known as a critical and noisy disease. Hyperglycemia, that is, increased blood glucose level is a common effect of uncontrolled diabetes, and over a period of time can cause serious effects on health such as blood vessel damage and nervous system damage. However, many attempts have been made to find suitable and beneficial solutions to overcome diabetes. Considering this fact, we synthesized a novel series of indoline-2,3-dione-based benzene sulfonamide derivatives and evaluated them against α-glucosidase and α-amylase enzymes. Out of the synthesized sixteen compounds (1-16), only three compounds showed better results; the IC50 value was in the range of 12.70 ± 0.20 to 0.90 ± 0.10 µM for α-glucosidase against acarbose 11.50 ± 0.30 µM and 14.90 ± 0.20 to 1.10 ± 0.10 µM for α-amylase against acarbose 12.20 ± 0.30 µM. Among the series, only three compounds showed better inhibitory potential such as analogues 11 (0.90 ± 0.10 µM for α-glucosidase and 1.10 ± 0.10 µM for α-amylase), 1 (1.10 ± 0.10 µM for α-glucosidase and 1.30 ± 0.10 µM for α-amylase), and 6 (1.20 ± 0.10 µM for α-glucosidase and 1.60 ± 0.10 µM for α-amylase). Molecular modeling was performed to determine the binding affinity of active interacting residues against these enzymes, and it was found that benzenesulfonohydrazide derivatives can be indexed as suitable inhibitors for diabetes mellitus.
RESUMEN
Aim: To synthesize pyrrolopyridine-based thiazolotriazoles as a novel class of α-amylase and α-glucosidase inhibitors and to determine their enzymatic kinetics. Methodology: Pyrrolopyridine-based thiazolotriazole analogs (1-24) were synthesized and characterized through proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and high-resolution electron ionization mass spectrometry. Results: All synthesized analogs displayed good inhibitory potential of α-amylase and α-glucosidase ranging 17.65-70.7 µM and 18.15-71.97 µM, respectively, compared with the reference drug, acarbose (11.98 µM and 12.79 µM). Analog 3 was the most potent among the synthesized analogs, having α-amylase and α-glucosidase inhibitory activity at 17.65 and 18.15 µM, respectively. The structure-activity relationship and binding modes of interactions between selected analogs were confirmed via docking and enzymatic kinetics studies. The compounds (1-24) were tested for cytotoxicity against the 3T3 mouse fibroblast cell line and were observed to be nontoxic.
Asunto(s)
Diabetes Mellitus , Compuestos Heterocíclicos , Animales , Ratones , Simulación del Acoplamiento Molecular , alfa-Glucosidasas/metabolismo , Cinética , Inhibidores de Glicósido Hidrolasas/química , Relación Estructura-Actividad , alfa-Amilasas , Estructura MolecularRESUMEN
A library of 2-oxopyridine carbonitriles 1-34 was synthesized by regioselective nucleophilic substitution reactions. In the first step, a one-pot multicomponent reaction yield pyridone intermediates. The resulting pyridone intermediates were then reacted with phenacyl halides in DMF and stirred at 100 °C for an hour to afford the desired compounds in good yields. Structures of synthetic molecules were characterized by EI-MS, HREI-MS, 1H NMR, and 13C NMR, and all thirty-four (34) compounds were found to be new. All synthetic compounds were examined for antidiabetic and antioxidant potential. The compounds exhibited α-glucosidase inhibitory potential in the range of IC50 = 3.00 ± 0.11-43.35 ± 0.67 µM and α-amylase inhibition potential in the range of IC50 = 9.20 ± 0.14-65.56 ± 1.05 µM. Among the tested compounds, 1 showed the most significant α-glucosidase inhibitory activity, with an IC50 value of 3.00 ± 0.11 µM, while the most active compound against α-amylase was 6, with an IC50 value = 9.20 ± 0.14 µM. The kinetic studies and analysis indicated that the compounds followed the competitive mode of inhibition. In addition, the molecular docking studies showed the interaction profile of all molecules with the binding site residues of α-glucosidase and α-amylase enzymes.
Asunto(s)
Antioxidantes , Hipoglucemiantes , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Antioxidantes/farmacología , Antioxidantes/química , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , alfa-Glucosidasas/metabolismo , Cinética , alfa-Amilasas/química , Piridonas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Estructura MolecularRESUMEN
The Wnt-ß-catenin signal transduction pathway is essential for embryonic development and adult tissue homeostasis. Wnt signaling converts TCF from a transcriptional repressor to an activator in a process facilitated by the E3 ligase XIAP. XIAP-mediated monoubiquitylation of the transcriptional corepressor Groucho (also known as TLE) decreases its affinity for TCF, thereby allowing the transcriptional coactivator ß-catenin to displace it on TCF. Through a genome-scale screen in cultured Drosophila melanogaster cells, we identified the deubiquitylase USP47 as a positive regulator of Wnt signaling. We found that USP47 was required for Wnt signaling during Drosophila and Xenopus laevis development, as well as in human cells, indicating evolutionary conservation. In human cells, knockdown of USP47 inhibited Wnt reporter activity, and USP47 acted downstream of the ß-catenin destruction complex. USP47 interacted with TLE3 and XIAP but did not alter their amounts; however, knockdown of USP47 enhanced XIAP-mediated ubiquitylation of TLE3. USP47 inhibited ubiquitylation of TLE3 by XIAP in vitro in a dose-dependent manner, suggesting that USP47 is the deubiquitylase that counteracts the E3 ligase activity of XIAP on TLE. Our data suggest a mechanism by which regulated ubiquitylation and deubiquitylation of TLE enhance the ability of ß-catenin to cycle on and off TCF, thereby helping to ensure that the expression of Wnt target genes continues only as long as the upstream signal is present.
Asunto(s)
Vía de Señalización Wnt , beta Catenina , Animales , Humanos , beta Catenina/metabolismo , Drosophila , Drosophila melanogaster/metabolismo , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , XenopusRESUMEN
This work reports the convenient approach for the synthesis of thiazole based thiourea derivatives (1-21) from 2-bromo-1-(4-fluorophenyl)thiazole-1-one and phenyl isothiocyanates. The scope and diversity were achieved from readily available phenyl isothiocyanates. This protocol involves an oxidative C-S bond formation. Moreover, hybrid thiazole based thiourea scaffolds (1-21) according to literature known protocol were screened in vitro for anticancer Potential against breast cancer, antiglycation and antioxidant inhibitory profile. All newly developed scaffolds were showed moderate to good inhibitory potentials ranging from 0.10 ± 0.01 µM to 11.40 ± 0.20 µM, 64.20 ± 0.40 µM to 385.10 ± 1.70 µM and 8.90 ± 0.20 µM to 39.20 ± 0.50 µM against anticancer, antiglycation and antioxidant respectively. Among the series, compounds 12 (IC50 = 0.10 ± 0.01 µM), 10 (IC50 = 64.20 ± 0.40 µM) and 12 (IC50 = 8.90 ± 0.20 µM) with flouro substitution at phenyl ring of thiourea were identified to be the most potent among the series having excellent anticancer, antiglycation and antioxidant potential. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, 1H- and 13C-NMR spectroscopy. To find structure-activity relationship, molecular docking studies were carried out to understand the binding mode of active inhibitors with active site of enzymes and results supported the experimental data.Communicated by Ramaswamy H. Sarma.