ABSTRACT
Targeting the enzymes of Pentose Phosphate Pathway (PPP) has been emerged as a novel strategy for treatment of cancer. 6-phosphogluconate dehydrogenase (6PGD) is third enzyme of PPP and converts 6-phosphogluconate (6-PG) into ribulose 5-phosphate (R-5-P) and produces NADPH. The overexpression of 6PGD has been reported in many human cancers especially in breast cancer and is emerged as the potential anti-cancer drug target. The current study is focused to screen an already established library of plant extracts against 6PGD, among which Pomegranate peel extract showed significant 6PGD inhibitory activity with IC50 value = 0.090 µg/mL. Pomegranate peel competitively inhibited NADP+ and 6-phosphogluconate to 6PGD enzyme having Ki constant value = 12.72 ± 5.54 ng/mL. Moreover, anti-breast cancer activity against MCF-7 cells determined Pomegranate peel as the potent inhibitor of cancerous cells with IC50 value = 3.138 µg/mL. Toxicity profiling of pomegranate peel extract (2000mg/kg) did not show any adverse effect on mice. Moreover, Ont the base of literature a library of known compounds of pomegranate was prepared and established and screened against 6PGD for the identification of actual responsible phytochemicals of 6PGD activity by using molecular docking. Computational tools were used to evaluate selected potent hits. Out of 26 compounds, three potent phytochemicals (Procyanidin, Delphinidin and Cyanidin) exhibited the best binding affinities with 6PGD. In addition, these phytochemicals displayed the best favorable hydrogen bonding, binding energy, and protein-ligand interactions as compare to 3PG. Molecular dynamics simulation suggested that these hits form a stable binding complex with the active site of 6PGD. These findings suggest that Pomegranate peel and its secondary metabolites as the potent inhibitors of 6PGD and the best drug candidate for treatment of breast cancer.
ABSTRACT
The urease enzyme is recognized as a valuable therapeutic agent for treating the virulent Helicobacter pylori bacterium because of its pivotal role in aiding the colonization and growth of the bacterium within the gastric mucosa. In order to control the harmful consequences of bacterial infections, urease inhibition presents itself as a promising and effective approach. The current research aimed to synthesize pyridylpiperazine-based carbodithioate derivatives 5a-5n and 7a-7n that could serve as potential drug candidates for preventing bacterial infections through urease inhibition. The synthesized carbodithioate derivatives 5a-5n and 7a-7n were explored to assess their ability to inhibit the urease enzyme after their structural explication by gas chromatography-mass spectrometry (GC-MS). In the in vitro evaluation with thiourea as a standard drug, it was observed that all the synthesized compounds exhibited significant inhibitory activity compared to the reference drug. Among the compounds tested, 5j (bearing an o-tolyl moiety) emerged as the most effective inhibitor, displaying strong urease inhibition with an IC50 value of 5.16 ± 2.68 µM. This IC50 value is notably lower than that of thiourea (23 ± 0.03 µM), indicating the significantly most potent potential of inhibition. In molecular docking of 5j within the active site of urease, numerous noteworthy interactions were identified.
ABSTRACT
The chemistry of nitrogen-containing heterocyclic compounds has been a multifaceted area of research for an extended period due to their varied therapeutic and biological significance. N-Aryl pyrrolidine formed by condensation of aryl group with nitrogen atom of pyrrolidine is present in a wide array of compounds. Various significant activities shown by N-arylated pyrrolidine include anti-Alzheimer, antihypoxic, anticancer, plant activator, analgesic effect, and hepatitis C inhibitor. This review summarizes different synthetic approaches, e.g., transition-metal catalyzed and transition-metal-free synthesis, decarboxylation reaction, reductive amination, nucleophilic cyclization, Ullmann-Goldberg amidation, Buchwald-Hartwig reaction, Chan-Evans-Lam coupling, addition to benzyne, multistep reaction, green synthesis, rearrangement reaction, and multicomponent reaction, to afford the derivatives of N-aryl pyrrolidine. It encompasses synthetic strategies documented from 2015 to 2023.
ABSTRACT
The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Heterocyclic Compounds , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/therapeutic use , SARS-CoV-2/drug effects , COVID-19ABSTRACT
Diabetes Mellitus is a metabolic disease characterized by elevated blood sugar levels caused by inadequate insulin production, which subsequently leads to hyperglycemia. This study was aimed to investigate the antidiabetic potential of pyrazolobenzothiazine derivatives in silico, in vitro, and in vivo. Molecular docking of pyrazolobenzothiazine derivatives was performed against α-glucosidase and α-amylase and compounds were selected based on docking score, bonding interactions and low root mean square deviation (RMSD). Enzyme inhibition assay against α-glucosidase and α-amylase was performed in vitro using p-nitrophenyl-α-D-glucopyranoside (PNPG) and starch substrate. Synthetic compound pyrazolobenzothiazine (S1) exhibited minimal conformational changes during the 100 ns MD simulation run. S1 also revealed effective IC50 values for α-glucosidase (3.91 µM) and α-amylase (8.89 µM) and an enzyme kinetic study showed low ki (- 0.186 µM, - 1.267 µM) and ki' (- 0.691 µM, - 1.78 µM) values with the competitive type of inhibition for both enzymes α-glucosidase and α-amylase, respectively. Moreover, studies were conducted to check the effect of the synthetic compound in a mouse model. A low necrosis rate was observed in the liver, kidney, and pancreas through histology analysis performed on mice. Compound S1 also exhibited a good biochemical profile with lower sugar level (110-115 mg/dL), increased insulin level (25-30 µM/L), and low level of cholesterol (85 mg/dL) and creatinine (0.6 mg/dL) in blood. The treated mice group also exhibited a low % of glycated haemoglobin (3%). This study concludes that S1 is a new antidiabetic-agent that helps lower blood glucose levels and minimizes the complications associated with type-II diabetes.
Subject(s)
Hyperglycemia , Hypoglycemic Agents , Mice , Animals , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemistry , alpha-Glucosidases/metabolism , Molecular Docking Simulation , Hyperglycemia/drug therapy , Insulin , alpha-Amylases/metabolism , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Urease, a nickel-dependent enzyme found in various life forms, catalyzes urea breakdown, concluding nitrogen metabolism by generating ammonia and carbamate. This process causes a rise in pH, supports the survival of pathogens, and can lead to infections such as gastric disorders like ulcers and cancer in humans. Helicobacter pylori employs urease for survival in the acidic environment of the stomach and in protein synthesis. To treat such infections and inhibit the growth of pathogens, it is mandatory to obstruct urease activity; therefore, derivatives of 1-(3-nitropyridin-2-yl)piperazine were synthesized (5a-o; 7a-k). All these newly synthesized compounds were investigated for urease inhibition by in vitro inhibition assays. The results showed that 5b and 7e are the most active inhibitors, having IC50 values of 2.0 ± 0.73 and 2.24 ± 1.63 µM, respectively. These IC50 values are lower than the IC50 value of the standard thiourea, which was 23.2 ± 11.0 µM. The hemolysis potential of 5b, 5c, 5i, 7e, and 7h was also determined; 7e and 7h exhibited good biocompatibility in human blood cells. Through in silico analysis, it was shown that both these potent inhibitors develop favorable interactions with the active site of urease, having binding energies of -8.0 (5b) and -8.1 (7e) kcal/mol. The binding energy of thiourea was -2.8 kcal/mol. Moreover, 5b and 7e have high gastrointestinal permeability as predicted via computational analysis. On the other hand, the IC50 value and binding energy of precursor compound 3 was 3.90 ± 1.91 µM and -6.1 kcal/mol, respectively. Consequently, 5b and 7e can serve as important inhibitors of urease.
ABSTRACT
Corrosion is a major problem that can lead to the degradation of metal structures. In this study, we developed a novel corrosion-protective coating for metal substrates based on a modified epoxy acrylate formulation reinforced with halloysite nanotubes (HNTs). Epoxy acrylate oligomers were first synthesized through the acrylation of epoxy using acrylic acid, followed by copolymerization with butyl methacrylate/vinyl acetate monomers to produce grafted epoxy acrylates (GEA). HNTs were then incorporated into the polymeric dispersion at weight loadings of 1%, 1.5%, and 2%. The corrosion resistance and waterproofing properties of the coatings were evaluated. The results showed that steel samples coated with HNTs-modified GEA showed no signs of rusting even after 16 days of immersion in a corrosive solution, whereas those coated with GEA alone showed rusting after only 9 days. These results demonstrate the effectiveness of HNTs-modified GEA coatings in protecting steel surfaces against corrosion. The coatings are also water-resistant and can be easily applied. This work provides a new approach to developing corrosion-protective coatings for metal substrates.
ABSTRACT
This study reports the interfacial phenomenon of cefotaxime in combination with nonionic surfactants, Triton X-100 (TX-100) and Tween-80 (TW-80), and their mixed micellar formulations. Cefotaxime was enclosed in a micellar system to improve its solubility and effectiveness. TX-100 and TW-80 were used in an amphiphilic self-assembly process to create the micellar formulation. The effect of the addition of TX-100, a nonionic surfactant, on the ability of TW-80 to solubilize the drug was examined. The values of the critical micelle concentration (CMC) were determined via UV-Visible spectroscopy. Gibbs free energies (ΔGp and ΔGb), the partition coefficient (Kx), and the binding constant (Kb) were also computed. In a single micellar system, the partition coefficient (Kx) was found to be 33.78 × 106 and 2.78 × 106 in the presence of TX-100 and TW-80, respectively. In a mixed micellar system, the value of the partition coefficient for the CEF/TW-80 system is maximum (5.48 × 106) in the presence of 0.0019 mM of TX-100, which shows that TX-100 significantly enhances the solubilizing power of micelles. It has been demonstrated that these surfactants are effective in enhancing the solubility and bioavailability of therapeutic compounds. This study elaborates on the physicochemical characteristics and solubilization of reactive drugs in single and mixed micellar media. This investigation, conducted in the presence of surfactants, shows a large contribution to the binding process via both hydrogen bonding and hydrophobic interactions.
ABSTRACT
In Parkinson's disease (PD), degradation of dopaminergic neurons in substantia nigra causes striatal deficiency of dopamine, which results in tremors, bradykinesia with instability in posture, rigidity and shuffled gait. Prevalence of PD increases with age as from 65 to 85 years. In an attempt to devise targeted safe therapy, nanoparticles of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (MBD) (MBDN), were prepared and their acute toxicity and safety was evaluated. Thirty-six healthy albino mice were randomly divided into six groups (n = 6): normal control, diseased control, standard (levodopa/carbidopa (100/25 mg/kg) and the remaining three groups were administered 1.25, 2.5 and 5 mg/kg MBDN during 21 days study. Except control, all mice, were injected haloperidol (1 mg/ kg i.p.) 1-h prior to treatment to induce PD. Acute toxicity test showed, no effect of MBDN on lipid profile, brain, renal and liver function and histoarchitecture of kidney, liver and heart, except decreased (p < 0.05) platelet count. Behavioral studies showed significant improvement (p < 0.001) in motor function and reduction of oxidation status in a MBDN in a dose dependent manner. Thus, the study findings revealed significance of MBDN as a selective MAO-B inhibitor for the improvement of Parkinson's symptoms in animal model.
Subject(s)
Parkinson Disease , Mice , Animals , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Haloperidol/toxicity , Haloperidol/therapeutic use , Dopamine/metabolism , Brain/metabolismABSTRACT
Introduction: Global public health concerns include the emergence and spread of methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase Escherichia coli (ESBL-E. coli). These pathogens cause infections that are difficult to treat, which can have fatal outcomes and require lengthy hospital stays. As a result, we created butyl 2-bromoisonicotinate and tested its antibacterial effectiveness against the ESBL-E. coli ST 405 and MRSA pathogens. Natural product discovery is complemented by synthetic compound synthesis because of the latter's potential for superior characteristics, target specificity, scalability, intellectual advantages, and chemical diversity. Because of this, the potential for discovering new medicinal compounds is increased, and the constraints placed on natural sources are overcome. Natural items are tough to obtain since they are hard to isolate and synthesize. Therefore, modern science is actively searching for small molecules as therapeutic agents by applying sustainable techniques that can be commercialized. Methods: Two patients' blood samples were taken, and the BACTEC/Alert system was used to process them. On blood and MacConkey agar, the positive samples were subcultured and incubated aerobically at 37 °C. Using the VITEK 2 compact system, the isolates were subjected to isolate identification and MIC. MLST of the ESBL-E. coli was performed by PCR. Additionally, Fischer esterification was used to create butyl 2-bromoisonicotinate in excellent yields. A commercially available palladium catalyst was then used to arylate the compound, resulting in medium to good yields of arylated butyl 2-bromoisonicotinates. Using the agar well diffusion assay and the micro-broth dilution method, we assessed the in-vitro activities of the synthesized molecules (3, 5a-h) against clinically isolated ESBL-E. coli ST405, and MRSA. A molecular operating environment was used to carry out in silico validation of the synthesized compounds' binding to the active site and to evaluate the stability of their molecular interactions with the target E. coli 2Y2T protein. Results: MRSA and ESBL-producing E. coli were identified as the two clinical isolates. While MRSA was also resistant to beta-lactam drugs and least resistant to vancomycin, ESBL-producing E. coli belonged to ST405 and was resistant to cephalosporins and sensitive to carbapenems. Good yields of the desired compounds were produced by our effective and economical synthesis. By using a micro-broth dilution assay, the Molecules (3, 5a, and 5d) were most effective against both resistant strains. The Molecules (3, 5a, 5b, and 5d) also displayed good binding energies. Conclusion: The butyl 2-bromoisonicotinate displayed antibacterial efficacy against ESBL-producing E. coli ST405 and MRSA strains. After the in-vivo trial, this substance might offer an alternative therapeutic option.
ABSTRACT
The ongoing COVID-19 pandemic has resulted in a global panic because of its continual evolution and recurring spikes. This serious malignancy is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the outbreak, millions of people have been affected from December 2019 till now, which has led to a great surge in finding treatments. Despite trying to handle the pandemic with the repurposing of some drugs, such as chloroquine, hydroxychloroquine, remdesivir, lopinavir, ivermectin, etc., against COVID-19, the SARS-CoV-2 virus continues its out-of-control spread. There is a dire need to identify a new regimen of natural products to combat the deadly viral disease. This article deals with the literature reports to date of natural products showing inhibitory activity towards SARS-CoV-2 through different approaches, such as in vivo, in vitro, and in silico studies. Natural compounds targeting the proteins of SARS-CoV-2-the main protease (Mpro), papain-like protease (PLpro), spike proteins, RNA-dependent RNA polymerase (RdRp), endoribonuclease, exoribonuclease, helicase, nucleocapsid, methyltransferase, adeno diphosphate (ADP) phosphatase, other nonstructural proteins, and envelope proteins-were extracted mainly from plants, and some were isolated from bacteria, algae, fungi, and a few marine organisms.
Subject(s)
Biological Products , COVID-19 , Humans , SARS-CoV-2/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , Pandemics , Biological Products/pharmacology , Biological Products/therapeutic use , Molecular Docking SimulationABSTRACT
Heterocyclic compounds are attractive candidates because of their vast applications in natural and physical sciences. Thienothiophene (TT) is an annulated ring of two thiophene rings with a stable and electron-rich structure. Thienothiophenes (TTs) fully represent the planar system, which can drastically alter or improve the fundamental properties of organic, π-conjugated materials when included into a molecular architecture. These molecules possessed many applications including, pharmaceutical as well as optoelectronic properties. Different isomeric forms of thienothiophene showed various applications such as antiviral, antitumor, antiglaucoma, antimicrobial, and as semiconductors, solar cells, organic field effect transistors, electroluminiscents etc. A number of methodologies were adopted to synthesize thienothiophene derivatives. In this review, we have addressed different synthetic strategies of various isomeric forms of thienothiophene that have been reported during last seven years, i.e., 2016-2022.
ABSTRACT
Toward the search for novel antimicrobial agents to control pathogenic E. coli-associated infections, a series of novel norfloxacin derivatives were screened for antimicrobial activities. The norfloxacin derivative, 1-ethyl-6-fluoro-7-(4-(2-(2-(3-hydroxybenzylidene)hydrazinyl)-2-oxoethyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (NF22) demonstrated excellent antibacterial activities against E. coli ATCC 25922 (MIC = 0.0625 µg/mL) and MDR E. coli 1-3 (MIC = 1, 2 and 1 µg/mL). The time-kill kinetic studies have demonstrated that the NF22 was advantageous over norfloxacin and ciprofloxacin in killing the control and MDR E. coli strains. The checkerboard assay showed that NF22 in combination with tetracycline had a synergistic effect against the E. coli strains. The experimental findings are supported by molecular modeling studies on DNA gyrase, explaining the interactions involved for compound NF22, compared to norfloxacin and ciprofloxacin. Further, the compound was also evaluated for various pharmacokinetics (absorption, metabolism, distribution, toxicity and excretion) as well as drug-likeness properties. Our data have highlighted the potential of norfloxacin by restoring its efficacy against E. coli which could lead to the development of new antimicrobial agents.
ABSTRACT
Micellar-enhanced ultrafiltration (MEUF), being a separation technique, was used to remove cobalt metal ion (Co2+) from their aqueous solutions in an application to reduce the toxicity level from industrial effluents using a micellar solution of anionic and cationic surfactants. The metal ions were first adsorbed by using anionic surfactants, i.e., sodium dodecyl sulfate (SDS) and sodium oleate (SO). The calculations for partition (Kx) and binding constants (Kb) and their respective free energy of partition and binding (ΔGp and ΔGb kJmol-1) helped significantly to find out the extent of binding or interaction of Co2+ with the surfactant and ΔGp and ΔGb were found to be -29.50 and -19.38 kJmol-1 for SDS and -23.95 and -12.67 kJmol-1 in the case of SO. MEUF work was also performed to find out the optimal conditions to remove metal pollutants from the aqueous system. For the said purpose, various factors and concentrations effect were studied, such as the concentration of the surfactant, concentration of the electrolyte (NaCl), transmembrane pressure, RPM, and pH. The efficiency of this process was checked by calculating various parameters, such as rejection percentage (R%) and permeate flux (J). A maximum rejection of 99.95% with SDS and 99.99% with SO was attained.
Subject(s)
Cobalt , Micelles , Ultrafiltration/methods , Sodium Dodecyl Sulfate , Surface-Active Agents , IonsABSTRACT
Cancer is a serious threat to human beings and is the second-largest cause of death all over the globe. Chemotherapy is one of the most common treatments for cancer; however, drug resistance and severe adverse effects are major problems associated with anticancer therapy. New compounds with multi-target inhibitory properties are targeted to surmount these challenges. Cyclooxygenase-2 (COX-2) is overexpressed in cancers of the pancreas, breast, colorectal, stomach, and lung carcinoma. Therefore, COX-2 is considered a significant target for the synthesis of new anticancer agents. This review discusses the biological activity of recently prepared dual anticancer and COX-2 inhibitory agents. The most important intermolecular interactions with the COX-2 enzyme have also been presented. Analysis of these agents in the active area of the COX-2 enzyme could guide the introduction of new lead compounds with extreme selectivity and minor side effects.
ABSTRACT
Purpose: The present study is based on screening new and potent synthetic heterocyclic compounds as anti-diabetic drugs using various computational tools, lab experiments, and animal models. Methods: A potent synthetic compound 2-(3-benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-1-(2-bromophenyl) acetamide (FA2) was checked against diabetes and screened via enzyme inhibition assays, enzyme kinetics against alpha-glucosidase and alpha-amylase. Protein-ligand interaction was analyzed via molecular docking and toxicological analysis via ADMET. Experimental animals were used to examine the compound FA2 safety, delivery, and check various biochemical tests related to diabetes like fasting glucose sugar, cholesterol, triglyceride, HbAc1, creatinine, and insulin level. Histography of liver, kidney, and pancreas was also performed. Results: Results showed that FA2 had binding energy of -7.02 Kcal/mol and -6.6 kcal/mol against α-glucosidase (PDB ID: 2ZE0) and α-amylase (PDB ID: 1B2Y), respectively. Moreover, in vitro enzyme inhibition assays and enzyme kinetics against α-glucosidase and α-amylase were performed, and FA2 showed IC50 at 5.17 ± 0.28 µM and 18.82 ± 0.89 µM concentrations against α-glucosidase and α-amylase, respectively. Kinetics studies showed that the FA2 compound impeded α-glucosidase and α-amylase as a non-competitive mode of inhibition with Ki' values -0.320 ± 0.001 and 0.141 ± 0.01, respectively. FA2 was further analyzed on alloxan-induced mice for 21 days. Biochemical tests (fasting glucose sugar, cholesterol, triglyceride, HbAc1, creatinine, and insulin levels) and histological examination of liver and kidney showed that the FA2 compound showed better results than acarbose. Histology of pancreas found to show the maintenance of normal pancreatic acini and Langerhans islets in FA2 treated mice compared to acarbose and nontreated diabetic controls. Conclusion: Investigating anti-diabetic potential of FA2 compound showed that the selected benzothiazine derivative has tremendous importance in reducing dose concentration and side effects.
Subject(s)
Acarbose , Insulins , Animals , Mice , alpha-Glucosidases , Creatinine , Molecular Docking Simulation , Hypoglycemic Agents/pharmacology , alpha-Amylases , Acetamides , Glucose , TriglyceridesABSTRACT
Tyrosine threonine kinase (TTK) is the key component of the spindle assembly checkpoint (SAC) that ensures correct attachment of chromosomes to the mitotic spindle and thereby their precise segregation into daughter cells by phosphorylating specific substrate proteins. The overexpression of TTK has been associated with various human malignancies, including breast, colorectal and thyroid carcinomas. TTK has been validated as a target for drug development, and several TTK inhibitors have been discovered. In this study, ligand and structure-based alignment as well as various partial charge models were used to perform 3D-QSAR modelling on 1H-Pyrrolo[3,2-c] pyridine core containing reported inhibitors of TTK protein using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches to design better active compounds. Different statistical methods i.e., correlation coefficient of non-cross validation (r2), correlation coefficient of leave-one-out cross-validation (q2), Fisher's test (F) and bootstrapping were used to validate the developed models. Out of several charge models and alignment-based approaches, Merck Molecular Force Field (MMFF94) charges using structure-based alignment yielded highly predictive CoMFA (q2 = 0.583, Predr2 = 0.751) and CoMSIA (q2 = 0.690, Predr2 = 0.767) models. The models exhibited that electrostatic, steric, HBA, HBD, and hydrophobic fields play a key role in structure activity relationship of these compounds. Using the contour maps information of the best predictive model, new compounds were designed and docked at the TTK active site to predict their plausible binding modes. The structural stability of the TTK complexes with new compounds was confirmed using MD simulations. The simulation studies revealed that all compounds formed stable complexes. Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.
ABSTRACT
The α-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. α-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its α-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better α-glucosidase inhibitions compared to the standard drug (acarbose IC50 = 58.8 ± 0.012 µM) with IC50 values of 15 ± 0.030, 19 ± 0.060, 25 ± 0.106, 21 ± 0.07 and 26 ± 0.035 µM, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand-receptor interactions.
Subject(s)
Diabetes Mellitus, Type 2 , Glycoside Hydrolase Inhibitors , Acarbose , Blood Glucose , Chlorides , Glycoside Hydrolase Inhibitors/pharmacology , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Morpholines , Salts/pharmacology , Structure-Activity Relationship , alpha-Glucosidases/metabolismABSTRACT
Diabetes mellitus (DM) is a metabolic disorder and a significant health problem all over the world. The current study elucidates the inhibitory potentials of the benzothiazine-pyrazole hybrid series against the α-Glucosidase enzyme. The molecular docking was employed to determine the binding affinity of synthetic compounds (ligands) with α-Glucosidase enzyme (receptor) active sites via the molecular operating environment (MOE). The molecular docking analysis revealed the best inhibitory interaction between certain synthetic compounds and the enzyme's active sites (α-Glucosidase). These compounds were further examined for drug-like properties, which necessarily validate the use of the compound as a drug. Then selected compounds were subjected to in vitro analysis to find the inhibitory potential with minimal dose. All compounds were docked into the active sites with the best binding pose and low rmsd values. The anti-diabetic analysis revealed that compound ST3 is more active against α-Glucosidase with IC50 values 5.8 µM as compared to acarbose which is 58.8 µM. The present study exhibited compound 2c has a high proficiency in lowering blood glucose levels compared to acarbose. This study strengthened the scope of designing/synthesizing these benzothiazine-pyrazole hybrid molecules as anti-diabetic drug molecules in the pharmaceutical industry.
ABSTRACT
Diabetes mellitus (DM) is a metabolic disorder that leads to hyperglycemia due to improper insulin secretion. The study aims to investigate the anti-diabetic potential of benzothiazine derivatives. Molecular docking and Molecular Dynamics simulation study revealed that Compound S6 (4-hydroxy-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide) and S7 (4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide) had less conformational changes during MD simulation analysis at 100 ns. Compound S6 and S7 showed potent activity with IC50 values of 5.93 µM, 6.91 µM and 75.17, 29.10 µM for α-glucosidase and α-amylase respectively and competitive type of inhibition was observed during enzyme kinetic study with a low value of Ki and Ki' for α-glucosidase and α-amylase, respectively. S6 has the lowest Ki (0.0736) and Ki' (-0.0982) for α-glucosidase. Furthermore, in vivo studies were carried out to distinguish the effects of the drug on the body. Histology analysis on mice model showed that compound S6 has a low necrosis rate in the liver, kidney, and pancreas compared to S7. Biochemical results of S6 revealed lower sugar level (112 mg/dL), increase insulin secretion (23, 25 µM/L), and low level of cholesterol (80, 85 mg/dL) and creatinine (1.6, 1.4 mg/dL). The results conclude that compound S6 is a new anti-diabetic agent that minimizes hyperglycemia complications.