We synthesized a series of novel 5-24 derivatives of oxindole. The synthesis started from 5-chlorooxindole, which was condensed with methyl 4-carboxybezoate and result in the formation of benzolyester derivatives of oxindole which was then treated with hydrazine hydrate. The oxindole benzoylhydrazide was treated with aryl acetophenones and aldehydes to get target compounds 5-24. The synthesized compounds were evaluated for urease inhibition; the compound 5 (IC50 = 13.00 ± 0.35 μM) and 11 (IC50 = 19.20 ± 0.50 μM) showed potent activity as compared to the standard drug thiourea (IC50 = 21.00 ± 0.01 μM). Other compounds showed moderate to weak activity. All synthetic compounds were characterized by different spectroscopic techniques including (1)H NMR, (13)C NMR, IR and EI MS. The molecular interactions of the active compounds within the binding site of urease enzyme were studied through molecular docking simulations.
Bisindole analogs 1-17 were synthesized and evaluated for their in vitro β-glucuronidase inhibitory potential. Out of seventeen compounds, the analog 1 (IC50=1.62±0.04 μM), 6 (IC50=1.86±0.05 μM), 10 (IC50=2.80±0.29 μM), 9 (IC50=3.10±0.28 μM), 14 (IC50=4.30±0.08 μM), 2 (IC50=18.40±0.09 μM), 19 (IC50=19.90±1.05 μM), 4 (IC50=20.90±0.62 μM), 7 (IC50=21.50±0.77 μM), and 3 (IC50=22.30±0.02 μM) showed superior β-glucuronidase inhibitory activity than the standard (d-saccharic acid 1,4-lactone, IC50=48.40±1.25 μM). In addition, molecular docking studies were performed to investigate the binding interactions of bisindole derivatives with the enzyme. This study has identified a new class of potent β-glucouronidase inhibitors.
Diabetes being a chronic metabolic disorder have attracted the attention of medicinal chemists and biologists. The introduction of new and potential drug candidates for the cure and treatment of diabetes has become a major concern due to its increased prevelance worldwide. In the current study, twenty-seven azachalcone derivatives 3-29 were synthesized and evaluated for their antihyperglycemic activities by inhibiting α-amylase and α-glucosidase enzymes. Five compounds 3 (IC50 = 23.08 ± 0.03 µM), (IC50 = 26.08 ± 0.43 µM), 5 (IC50 = 24.57 ± 0.07 µM), (IC50 = 27.57 ± 0.07 µM), 6 (IC50 = 24.94 ± 0.12 µM), (IC50 = 27.13 ± 0.08 µM), 16 (IC50 = 27.57 ± 0.07 µM), (IC50 = 29.13 ± 0.18 µM), and 28 (IC50 = 26.94 ± 0.12 µM) (IC50 = 27.99 ± 0.09 µM) demonstrated good inhibitory activities against α-amylase and α-glucosidase enzymes, respectively. Acarbose was used as the standard in this study. Structure-activity relationship was established by considering the parent skeleton and different substitutions on aryl ring. The compounds were also subjected for kinetic studies to study their mechanism of action and they showed competitive mode of inhibition against both enzymes. The molecular docking studies have supported the results and showed that these compounds have been involved in various binding interactions within the active site of enzyme.
Novel ibuprofen derivatives 1-19 including ibuprofen hydrazide 1, and substituted thiourea derivatives 2-19 were synthesized and characterized by EI-MS, FAB-MS, HREI-MS, HRFAB-MS, 1H-, and 13C-NMR spectroscopic techniques. The synthetic molecules 1-19 were examined for their in vitro urease inhibition and were found to display a diversified degree of inhibitory potential in the range of IC50 = 2.96-178 μM as compared to the standard thiourea (IC50 = 21.32 ± 0.22 μM). Out of nineteen, thirteen derivatives 2-4, 6, 7, 9, 11-15, 17, and 18 demonstrated remarkable inhibitory activity with IC50 values of 2.96 ± 1.11 to 16.1 ± 1.07 μM, compound 5 exhibited moderate inhibition with IC50 value of 37.3 ± 0.41 μM, whereas, compounds 1, 8, and 10 demonstrated weak inhibition against urease enzyme. Almost all structural features are participating in the activity; however, limited structure-activity relationship was discussed on the basis of different structural features, i.e., different functional groups and their positions at aryl part. In addition, molecular docking study was performed in order to understand the ligands binding interactions with the active site of urease enzyme.
Thymidine phosphorylase (TP) is up regulated in wide variety of solid tumors and therefore presents a remarkable target for drug discovery in cancer. A novel class of extremely potent TPase inhibitors based on benzopyrazine (1-28) has been developed and evaluated against thymidine phosphorylase enzyme. Out of these twenty-eight analogs eleven (11) compounds 1, 4, 14, 15, 16, 17, 18, 19, 20, 24 and 28 showed potent thymidine phosphorylase inhibitory potentials with IC50 values ranged between 3.20±0.30 and 37.60±1.15μM when compared with the standard 7-Deazaxanthine (IC50=38.68±4.42μM). Structure-activity relationship was established and molecular docking studies were performed to determine the binding interactions of these newly synthesized compounds. Current studies have revealed that these compounds established stronger hydrogen bonding networks with active site residues as compare to the standard compound 7DX.
Current study based on the synthesis of new thiazole derivatives via "one pot" multicomponent reaction, evaluation of their in vitro α-glucosidase inhibitory activities, and in silico studies. All synthetic compounds were fully characterized by (1)H NMR, (13)C NMR and EIMS. CHN analysis was also performed. These newly synthesized compounds showed activities in the range of IC50=9.06±0.10-82.50±1.70μM as compared to standard acarbose (IC50=38.25±0.12μM). It is worth mentioning that most of the compounds such as 1 (IC50=23.60±0.39μM), 2 (IC50=22.70±0.60μM), 3 (IC50=22.40±0.32μM), 4 (IC50=26.5±0.40μM), 6 (IC50=34.60±0.60μM), 7 (IC50=26.20±0.43μM), 8 (IC50=14.06±0.18μM), 9 (IC50=17.60±0.28μM), 10 (IC50=27.16±0.41μM), 11 (IC50=19.16±0.19μM), 12 (IC50=9.06±0.10μM), 13 (IC50=12.80±0.21μM), 14 (IC50=11.94±0.18μM), 15 (IC50=16.90±0.20μM), 16 (IC50=12.60±0.14μM), 17 (IC50=16.30±0.29μM), and 18 (IC50=32.60±0.61μM) exhibited potent inhibitory potential. Molecular docking study was performed in order to understand the molecular interactions between the molecule and enzyme. Newly identified α-glucosidase inhibitors except few were found to be completely non-toxic.
Coumarin sulfonates 4-43 were synthesized by reacting 3-hydroxy coumarin 1, 4-hydroxy coumarin 2and6-hydroxy coumarin 3 with different substituted sulfonyl chlorides and subjected to evaluate for their in vitro immunomodulatory potential. The compounds were investigated for their effect on oxidative burst activity of zymosan stimulated whole blood phagocytes using a luminol enhanced chemiluminescence technique. Ibuprofen was used as standard drug (IC50=54.2±9.2μM). Eleven compounds 6 (IC50=46.60±14.6μM), 8 (IC50=11.50±6.5μM), 15 (IC50=21.40±12.2μM), 19 (IC50=5.75±0.86μM), 22 (IC50=10.27±1.06μM), 23 (IC50=33.09±5.61μM), 24 (IC50=4.93±0.58μM), 25 (IC50=21.96±14.74μM), 29 (IC50=12.47±9.2μM), 35 (IC50=20.20±13.4μM) and 37 (IC50=14.47±5.02μM) out of forty demonstrated their potential suppressive effect on production of reactive oxygen species (ROS) as compared to ibuprofen. All the synthetic derivatives 4-43 were characterized by different available spectroscopic techniques such as 1H NMR, 13C NMR, EIMS and HRMS. CHN analysis was also performed.
Diabetes is associated with neurodegeneration. Glycation ensues in diabetes and glycated proteins cause insulin resistance in brain resulting in amyloid plaques and NFTs. Also glycation enhances gliosis by promoting neuroinflammation. Currently there is no therapy available to target neurodegenration in brain therefore, development of new therapy that offers neuroprotection is critical. The objective of this study was to evaluate mechanistic effect of isatin derivative URM-II-81, an anti-glycation agent for improvement of insulin action in brain and inhibition of neurodegenration. Methylglyoxal induced stress was inhibited by treatment with URM-II-81. Also, Ser473 and Ser9 phosphorylation of Akt and GSK-3β respectively were restored by URM-II-81. Effect of URM-II-81 on axonal integrity was studied by differentiating Neuro2A using retinoic acid. URM-II-81 restored axonal length in MGO treated cells. Its effects were also studied in high fat and low dose streptozotocin induced diabetic mice where it reduced RBG levels and inhibited glycative stress by reducing HbA1c. URM-II-81 treatment also showed inhibition of gliosis in hippocampus. Histological analysis showed reduced NFTs in CA3 hippocampal region and restoration of insulin signaling in hippocampii of diabetic mice. Our findings suggest that URM-II-81 can be developed as a new therapeutic agent for treatment of neurodegenration.
α-Glucosidase is a catabolic enzyme that regulates the body's plasma glucose levels by providing energy sources to maintain healthy functioning. 2-Amino-thiadiazole (1-13) and 2-amino-thiadiazole based Schiff bases (14-22) were synthesized, characterized by 1H NMR and HREI-MS and screened for α-glucosidase inhibitory activity. All twenty-two (22) analogs exhibit varied degree of α-glucosidase inhibitory potential with IC50 values ranging between 2.30 ± 0.1 to 38.30 ± 0.7 μM, when compare with standard drug acarbose having IC50 value of 39.60 ± 0.70 μM. Among the series eight derivatives 1, 2, 6, 7, 14, 17, 19 and 20 showed outstanding α-glucosidase inhibitory potential with IC50 values of 3.30 ± 0.1, 5.80 ± 0.2, 2.30 ± 0.1, 2.70 ± 0.1, 2.30 ± 0.1, 5.50 ± 0.1, 4.70 ± 0.2, and 5.50 ± 0.2 μM respectively, which is many fold better than the standard drug acarbose. The remaining analogs showed good to excellent α-glucosidase inhibition. Structure activity relationship has been established for all compounds. The binding interactions of these compounds were confirmed through molecular docking.
Discovery of α-glucosidase inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of type-II diabetes mellitus and the other carbohydrate mediated disease. In continuation of our drug discovery research on potential antidiabetic agents, we synthesized novel tris-indole-oxadiazole hybrid analogs (1-21), structurally characterized by various spectroscopic techniques such as 1H NMR, EI-MS, and 13C NMR. Elemental analysis was found in agreement with the calculated values. All compounds were evaluated for α-glucosidase inhibiting potential and showed potent inhibitory activity in the range of IC50=2.00±0.01-292.40±3.16μM as compared to standard acarbose (IC50=895.09±2.04µM). The pharmacokinetic predictions of tris-indole series using descriptor properties showed that almost all compounds in this series indicate the drug aptness. Detailed binding mode analyses with docking simulation was also carried out which showed that the inhibitors can be stabilized by the formation of hydrogen bonds with catalytic residues and the establishment of hydrophobic contacts at the opposite side of the active site.
In search of better α-glucosidase inhibitors, a series of bis-indolylmethane sulfonohydrazides derivatives (1-14) were synthesized and evaluated for their α-glucosidase inhibitory potential. All derivatives exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 0.10 ± 0.05 to 5.1 ± 0.05 μM when compared with standard drug acarbose having IC50 value 856.28 ± 3.15 μM. Among the series, analog 7 (0.10 ± 0.05 μM) with tri-chloro substitution on phenyl ring was identified as the most potent inhibitor of α-glucosidase (∼ 8500 times). The structure activity relationship has been also established. Molecular docking studies were also performed to help understand the binding interaction of the most active analogs with receptors. From the docking studies, it was observed that all the active bis-indolylmethane sulfonohydrazides derivatives showed considerable binding interactions within the active site (acarbose inhibition site) of α-glucosidase. We also evaluated toxicity of all derivatives and found none of them are toxic.
Current research is based on the synthesis of novel (E)-4-aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazole derivatives (3-15) by adopting two steps route. First step was the condensation between the pyrene-1-carbaldehyde (1) with the thiosemicarbazide to afford pyrene-1-thiosemicarbazone intermediate (2). While in second step, cyclization between the intermediate (2) and phenacyl bromide derivatives or 2-bromo ethyl acetate was carried out. Synthetic derivatives were structurally characterized by spectroscopic techniques such as EI-MS, 1H NMR and 13C NMR. Stereochemistry of the iminic double bond was confirmed by NOESY analysis. All pure compounds 2-15 were subjected for in vitro β-glucuronidase inhibitory activity. All molecules were exhibited excellent inhibition in the range of IC50=3.10±0.10-40.10±0.90μM and found to be even more potent than the standard d-saccharic acid 1,4-lactone (IC50=48.38±1.05μM). Molecular docking studies were carried out to verify the structure-activity relationship. A good correlation was perceived between the docking study and biological evaluation of active compounds.
Acarbose and voglibose are well-known α-amylase inhibitors used for the management of type-II diabetes mellitus. Unfortunately, these well-known and clinically used inhibitors are also associated with several adverse effects. Therefore, there is still need to develop the safer therapy. Despite of a broad spectrum of biological significances of pyrazolone, it is infrequently evaluated for α-amylase inhibition. Current study deals with the synthesis and biological screening of aryl and arylidene substituted pyrazolones 1-18 for their potential α-amylase inhibitory activity. Structures of synthetic derivatives 1-18 were identified by different spectroscopic techniques. All compounds 1-18 (IC50 = 1.61 ± 0.16 μM to 2.38 ± 0.09 μM) exhibited significant to moderate inhibitory potential when compared to standard acarbose (IC50 = 1.46 ± 0.26 μM). A number of derivatives including 8-12 (IC50 = 1.68 ± 0.1 μM to 1.97 ± 0.07 μM) and 14-16 (IC50 = 1.61 ± 0.16 μM to 1.93 ± 0.07 μM) were found to be significantly active. Limited SAR suggested that different substitutions on compounds do not have any significant effect on the inhibitory potential. Compounds were found to be mixed-type inhibitors revealed by kinetic studies. However, in silico study was identified a number of key features participating in the interaction with the binding site of α-amylase enzyme.
Urease is a bacterial enzyme that is responsible for virulence of various pathogenic bacteria such as Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae, Ureaplasma urealyticum, Helicobacter pylori and Mycobacterium tuberculosis. Increased urease activity aids in survival and colonization of pathogenic bacteria causing several disorders especially gastric ulceration. Hence, urease inhibitors are used for treatment of such diseases. In search of new molecules with better urease inhibitory activity, herein we report a series of acridine derived (thio)semicarbazones (4a-4e, 6a-6l) that were found to be active against urease enzyme. Molecular docking studies were carried out to better comprehend the preferential mode of binding of these compounds against urease enzyme. Docking against urease from pathogenic bacterium S. pasteurii was also carried out with favorable results. In silico ADME evaluation was done to determine drug likeness of synthesized compounds.
Novel derivatives of flurbiprofen 1-18 including flurbiprofen hydrazide 1, substituted aroyl hydrazides 2-9, 2-mercapto oxadiazole derivative 10, phenacyl substituted 2-mercapto oxadiazole derivatives 11-15, and benzyl substituted 2-mercapto oxadiazole derivatives 16-18 were synthesized and characterized by EI-MS, 1H and 13C NMR spectroscopic techniques. All derivatives 1-18 were screened for α-amylase inhibitory activity and demonstrated a varying degree of potential ranging from IC50 = 1.04 ± 0.3 to 2.41 ± 0.09 µM as compared to the standard acarbose (IC50 = 0.9 ± 0.04 µM). Out of eighteen compounds, derivatives 2 (IC50 = 1.69 ± 0.1 µM), 3 (IC50 = 1.04 ± 0.3 µM), 9 (IC50 = 1.25 ± 1.05 µM), and 13 (IC50 = 1.6 ± 0.18 µM) found to be excellent inhibitors while rest of the compounds demonstrated comparable inhibition potential. A limited structure-activity relationship (SAR) was established by looking at the varying structural features of the library. In addition to that, in silico study was conducted to understand the binding interactions of the compounds (ligands) with the active site of α-amylase enzyme.
The biological, chemical, and in silico properties of methanol and dichloromethane (DCM) extracts of Alhagi maurorum roots with respect to the antioxidant, enzyme inhibition, and phytochemical composition were evaluated. Total bioactive contents were determined spectrophotometrically, and the individual secondary metabolites composition was assessed via ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) analysis. Antioxidant capacities were evaluated using a panoply of assays (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging, ferric reducing antioxidant power (FRAP), cupric reducing antioxidant power (CUPRAC), phosphomolybdenum total antioxidant capacity (TAC), and metal chelating activity (MCA)). The enzyme inhibition potential was studied against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase, α-glucosidase, tyrosinase, urease and lipoxygenase (LOX) enzymes. The methanol extract was found to contain higher total phenolic (105.91 mg GAE/g extract) and flavonoid (2.27 mg RE/g extract) contents which can be correlated to its more substantial antioxidant potential as well as AChE, BChE, tyrosinase and α-glucosidase inhibition. However, the DCM extract was the most effective against α-amylase (1.86 mmol ACAE/g extract) enzyme inhibition. The UHPLC-MS analysis of methanol extract identified the tentative presence of a total of 18 secondary metabolites, including flavonoids, saponins, phenolic and terpenoid derivatives. Three compounds named emmotin A, luteolin 5,3'-dimethyl ether, and preferrugone were further investigated for their in silico molecular docking studies against the tested enzymes. The selected compounds were found to have higher binding interaction with AChE followed by BChE, α-glucosidase, α-amylase, and tyrosinase. The results of the present study have demonstrated A. mauroram to be considered as a lead source of natural antioxidant and enzyme inhibitor compounds.
3,4-Dimethoxybenzohydrazide derivatives (1-25) have been synthesized and evaluated for their urease inhibitory potential. Among the series, compounds 2, 3, 4 and 5 with IC50 values 12.61 ± 0.07, 18.24 ± 0.14, 19.22 ± 0.21, and 8.40 ± 0.05 µM, respectively, showed excellent urease inhibitory potentials when compared with standard thiourea (IC50 value 21.40 ± 0.21 µM). Compounds 1, 6, 8, 18, 19 and 20 also showed good to moderate inhibition, while the remaining compounds were found to be completely inactive. The structures of compounds 6 and 25 were confirmed through X-ray crystallography while the structures of remaining compounds were confirmed through ESI-MS and 1H NMR. Molecular docking studies were performed understand the binding interactions with enzyme active site. The synthesized compounds were evaluated for cytotoxicity and found to be nontoxic.
Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.
Hybrid bisindole-thiosemicarbazides analogs (1-18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC50 values ranging from 0.1 to 5.7μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC50 values ranging from 7.12 to 15.0μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC50 values 33.2±0.75, 21.4±0.30 and 28.12±0.25μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds.
Despite of many diverse biological activities exhibited by benzimidazole scaffold, it is rarely explored for the α-amylase inhibitory activity. For that purpose, 2-aryl benzimidazole derivatives 1-45 were synthesized and screened for in vitro α-amylase inhibitory activity. Structures of all synthetic compounds were deduced by various spectroscopic techniques. All compounds revealed inhibition potential with IC50 values of 1.48 ± 0.38-2.99 ± 0.14 μM, when compared to the standard acarbose (IC50 = 1.46 ± 0.26 μM). Limited SAR suggested that the variation in the inhibitory activities of the compounds are the result of different substitutions on aryl ring. In order to rationalize the binding interactions of most active compounds with the active site of α-amylase enzyme, in silico study was conducted.