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1.
J Biomol Struct Dyn ; : 1-18, 2023 Jul 30.
Article in English | MEDLINE | ID: mdl-37517055

ABSTRACT

A series of halogen-substituted aurone derivatives (2a-k) were synthesized and evaluated for an anti-proliferative study against NCI 60 cancer cell line panel and showed that most of the compounds predominantly exhibited promising activity against MCF-7. Compound 2e exhibited promising anticancer activity against the MCF-7 cancer cell line with 84.98% percentage growth inhibition in a single dose assay of 10 µM with an IC50 value of 8.157 ± 0.713 µM. In apoptotic assay, the effect of compound 2e on the cell cycle progression indicated that exposure of MCF-7 cells to compound 2e induced a significant disruption in the cell cycle profile including a time-dependent decrease in the cell population at G0/G1 and G2/M phase and arrests the cell cycle at the S phase. In silico, molecular docking ADME and toxicity studies of all compounds were also carried out. The docking study revealed that all the aurone derivatives displayed good docking scores ranging from -7.066 to -8.573. The results of Molecular Electrostatic Potential Mapping (MESP) and Density Functional Theory (DFT) studies of the most active compound 2e and least active compound 2k also favoured the experimental results.

2.
J Biomol Struct Dyn ; 41(22): 13466-13487, 2023.
Article in English | MEDLINE | ID: mdl-36856061

ABSTRACT

A series of novel 5-chloro-6-methylaurone derivatives (6a-p) were synthesized and characterized by various spectroscopic techniques. The synthesized compounds were tested for anticancer activity against 60-human cancer cell line panel derived from nine cancer types at NCI, Bethesda, USA. Among the synthesized compounds, six compounds (6e, 6f, 6h, 6i, 6k and 6 m) exhibited growth inhibition and cytotoxic activity against various human cancer cell lines in one-dose data. The most potent compound among the series, 6i was active against 55 out of 60 human cancer cell lines. Compound 6i showed remarkable % growth inhibition and cytotoxicity against various cancer cell lines exhibiting % GI in the range 36.05-199.03. The compound 6i was further evaluated for five dose assay and exhibited GI50 1.90 µM and 2.70 µM against melanoma and breast cancer cell lines respectively. Further evaluation of 6i for five-dose assay exhibited a diverse spectrum of anti-cancer activity towards all the 60 human cancer cell line panel with the selectivity index ratio ranging 0.854-1.42 and 0.66-1.35 for GI50 and TGI respectively. Based on one-dose and five-dose data compound 6i was further evaluated for cell apoptosis against MDA-MB-468 breast cancer cell line and was found to induce early apoptosis in cells explaining its mode of action. The in-silico studies for the synthesized compounds as LSD1 inhibitors (2H94) have shown better docking score and binding energy comparable to vafidemstat. All the compounds followed Lipinski rule of five. These findings concluded that the compound 6i could lead to the development of a promising therapeutic anticancer agent.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Humans , Female , Structure-Activity Relationship , Cell Line, Tumor , Drug Screening Assays, Antitumor , Cell Proliferation , Molecular Docking Simulation , Antineoplastic Agents/chemistry , Molecular Structure
3.
J Enzyme Inhib Med Chem ; 38(1): 2189126, 2023 12.
Article in English | MEDLINE | ID: mdl-36950918

ABSTRACT

A series of 20 newly designed (E)-1-(4-sulphamoylphenylethyl)-3-arylidene-5-aryl-1H-pyrrol-2(3H)-ones was synthesised and assessed as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors towards four human isoforms of pharmaceutical interest, that is, hCA I, II, IX and XII. The compounds displayed low to high nanomolar potency against all the isoforms. Introducing strong electron withdrawing groups at the para position of the arylidene ring increased the binding affinity to the enzyme. All compounds showed acceptable pharmacokinetic range and physicochemical characteristics as determined by computational ADMET analysis. Density Functional Theory (DFT) calculations of 3n were carried to gain understanding on the stability of the E and Z isomers. The energy values clearly indicate the stability of E isomer over Z isomer by -8.2 kJ mol-1. Our findings indicate that these molecules are useful as leads for discovering new CA inhibitors.


Subject(s)
Antigens, Neoplasm , Carbonic Anhydrases , Humans , Carbonic Anhydrase IX , Antigens, Neoplasm/metabolism , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/metabolism , Models, Theoretical , Structure-Activity Relationship , Molecular Structure
4.
ACS Omega ; 8(7): 6650-6662, 2023 Feb 21.
Article in English | MEDLINE | ID: mdl-36844525

ABSTRACT

Six 1,4-benzothiazin-3-ones (2a-f) and four benzothiazinyl acetate derivatives (3a-d) were synthesized and characterized by various spectroscopic methods, namely, 1H NMR, 13C NMR, IR, MS, and elemental analysis. The cytotoxic effects of the compounds were assessed against MCF-7, a human breast cancer cell line, along with their anti-inflammatory activity. Molecular docking studies performed against the VEGFR2 kinase receptor displayed a common binding orientation of the compounds in the catalytic binding pocket of the receptor. The generalized Born surface area (GBSA) studies of compound 2c with the highest docking score also proved its stability in binding to the kinase receptor. Compounds 2c and 2b showed better results against VEGFR2 kinase with IC50 values of 0.0528 and 0.0593 µM, respectively, compared to sorafenib. All of the compounds (2a-f and 3a-d) showed effective growth inhibition having (IC50) values of 2.26, 1.37, 1.29, 2.30, 4.98, 3.7, 5.19, 4.50, 4.39, and 3.31 µM, respectively, against the MCF-7 cell line compared to standard 5-fluorouracil (IC50 = 7.79 µM). However, compound 2c displayed remarkable cytotoxic activity (IC50 = 1.29 µM), suggesting it as a lead compound in the cytotoxic assay. Additionally, compounds 2c and 2b showed better results against VEGFR2 kinase with IC50 values of 0.0528 and 0.0593 µM, respectively, compared to sorafenib. It also inhibited hemolysis by stabilizing the membrane comparable to that of diclofenac sodium, a standard used in the human red blood cell membrane stabilization assay and hence can act as a template for designing novel anticancer and anti-inflammatory agents.

5.
Bioorg Med Chem Lett ; 28(7): 1198-1206, 2018 04 15.
Article in English | MEDLINE | ID: mdl-29525219

ABSTRACT

Gram-positive bacteria are among the most common human pathogens associated with clinical infections which range from mild skin infections to sepsis. Resistance towards existing class of drugs by Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE) is a growing concern. There is an urgent need to discover new antibiotics which are active against resistant strains of Gram positive bacteria. We report herein a novel class of spiropyrimidinetrione oxazolidinone derivatives as novel antibacterial agents. Key step towards the synthesis of title compounds involved the use of tert-amino reaction with [1,5]-hydride shift leading to the new CC bond formation. Compound 30n has demonstrated potent antibacterial activity against a panel of Gram-positive microbial strains including MRSA, MRSE, and LNZ and vancomycin resistant strains of E. faecalis. Further, molecular docking studies suggest that 30n has binding mode similar to that of LNZ in 50S RNA ribosome.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Design , Oxazolidinones/pharmacology , Pyrimidinones/pharmacology , Spiro Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Staphylococcus epidermidis/drug effects , Structure-Activity Relationship , Vancomycin-Resistant Enterococci/drug effects
6.
ACS Appl Mater Interfaces ; 8(30): 19716-23, 2016 Aug 03.
Article in English | MEDLINE | ID: mdl-27378322

ABSTRACT

Riluzole is the only available drug for motor neuron diseases quite well-known for its neuroprotective activity. But its poor aqueous solubility, short half-life with some side-effects at higher concentration poses a limitation to its use as a therapeutic agent. The present study was performed to investigate the therapeutic potential of nanoriluzole (NR), i.e., riluzole encapsulated in nanoparticles against cerebral ischemia (stroke) at three different concentrations [10 (NRL), 20 (NRM), and 40 (NRH) µg/kg body weight intraperitoneally (i.p.)]. Chitosan conjugated NIPAAM (N-isopropylacrylamide) nanoparticles coated with tween80 were synthesized through free radical polymerization. The particles were characterized with Transmission Electron Microscopy, Dynamic Light Scattering, and Fourier Transform Infrared spectroscopy and were found to have size of ∼50 nm. Cerebral ischemia was induced by Middle Cerebral Artery Occlusion (MCAO) model for 1 h and NR was given intraperitoneally after 1 h of MCAO. Animals were dissected after a reperfusion period of 24 h for evaluation of various parameters. Triphenyl tetrazolium chloride staining shows substantial reduction in infarct size in all three treated groups. It was also supported by histopathological results, biochemical parameters, and behavioral studies. Immunological parameters like NOS-2, NF-kB, and COX-2 also show profound reduction in expression in NR treated groups. Thus, the present work clearly demonstrated that the nanoparticle was good enough to carry large amount of drug across the Blood Brain Barrier which results in significant neuroprotection even at a very low concentration. It also substantially lowered the required concentration by overcoming the poor aqueous solubility; hence hardly leaving any scope for side-effects.


Subject(s)
Brain Ischemia/drug therapy , Drug Delivery Systems , Riluzole/administration & dosage , Animals , Brain/drug effects , Male , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Rats , Rats, Wistar , Riluzole/chemistry , Riluzole/pharmacology
7.
J Biomed Nanotechnol ; 12(2): 274-85, 2016 Feb.
Article in English | MEDLINE | ID: mdl-27305761

ABSTRACT

Liver fibrosis is the common response to chronic liver injury and ultimately leads to cirrhosis. There is a pressing need in the pharmaceutical industry to develop efficient well-targeted drug delivery systems, which are lacking to date. This study was designed to investigate the efficacy of a nanoquercetin NQ; i.e., quercetin encapsulated in PAG (p-aminophenyl-1-thio-ß-D-galactopryranoside)-coated NIPAAM (N-isopropyl acrylamide) nanopolymer in liver compared with naked quercetin (Q) using a carbon tetrachloride (CCl4)-mediated liver cirrhosis model. NQ was more effective at restoring liver membrane integrity as indicated by significantly reduced serum markers, including Alanine Transaminase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH), compared with naked Q. The findings of reduced collagen and histopathology also show that the NQ effects were much better than those of naked Q. Biochemical parameters, including antioxidant defense enzymes, also provide supporting evidence. Furthermore, the decrease in NF-κB and NOS-2 expression in the NQ-treated groups was also much stronger than in the naked Q-treated group. Thus, the data clearly suggest that NQ not only provides significant hepatoprotection compared with naked Q, but it also substantially lowered the required concentration (1,000 to 10,000-fold lower) by increasing the bioavailability.


Subject(s)
Drug Delivery Systems , Liver Cirrhosis/chemically induced , Liver Cirrhosis/drug therapy , Nanoparticles/chemistry , Quercetin/administration & dosage , Quercetin/therapeutic use , Acrylamides/chemistry , Alanine Transaminase , Alkaline Phosphatase/blood , Animals , Antioxidants/metabolism , Aspartate Aminotransferases/blood , Body Weight/drug effects , Carbon Tetrachloride , Collagen/metabolism , Dynamic Light Scattering , Immunohistochemistry , Kinetics , L-Lactate Dehydrogenase/blood , Liver/drug effects , Liver/pathology , Liver Cirrhosis/blood , Liver Cirrhosis/enzymology , Magnetic Resonance Spectroscopy , Male , Monosaccharides/chemistry , NF-kappa B/metabolism , Nanoparticles/ultrastructure , Nitric Oxide Synthase Type II/metabolism , Organ Size/drug effects , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Thiobarbituric Acid Reactive Substances/metabolism
8.
Chem Biol Drug Des ; 88(3): 354-62, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27037532

ABSTRACT

Piperine is an alkaloid responsible for the pungency of black pepper. In this study, piperine isolated from Piper nigrum L. was hydrolyzed under basic condition to obtain piperic acid and was used as precursor to carry out the synthesis of twenty piperine derivatives containing benzothiazole moiety. All the benzothiazole derivatives were evaluated for their antidiabetic potential by OGT test followed by assessment of active derivatives on STZ-induced diabetic model. It was observed that nine of twenty novel piperine analogues (5b, 6a-h), showed significantly higher antidiabetic activity in comparison with rosiglitazone (standard). Furthermore, these active derivatives were evaluated for their action as PPAR-γ agonists demonstrating their mechanism of action. The effects on body weight, lipid peroxidation, and hepatotoxicity after administration with active derivatives were also studied to further establish these derivatives as lead molecules for treatment of diabetes with lesser side-effects.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , PPAR gamma/agonists , Piperidines/chemistry , Piperidines/therapeutic use , Animals , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Gene Expression Regulation/drug effects , HEK293 Cells , Humans , Hypoglycemic Agents/pharmacology , Lipid Peroxidation/drug effects , Male , Molecular Docking Simulation , PPAR gamma/genetics , PPAR gamma/metabolism , Piper nigrum/chemistry , Piperidines/pharmacology , Rats, Wistar
9.
J Enzyme Inhib Med Chem ; 31(6): 1415-27, 2016 Dec.
Article in English | MEDLINE | ID: mdl-26879420

ABSTRACT

Thirty new aryl-pyridazinone-substituted benzenesulphonylurea derivatives (I-XXX) were synthesized and evaluated for their anti-hyperglycaemic activity in glucose-fed hyperglycaemic normal rats. Twenty-three compounds (III-XI, XIV-XVII, XIX-XXIV, XXVI and XXVIII-XXX) showed more or comparable area under the curve (AUC) reduction percentage (ranging from 21.9% to 35.5%) as compared to the standard drug gliclazide (22.0%). On the basis of docking results, 18 compounds were screened for their in vitro ability to inhibit rat lens aldose reductase. Ten compounds (III-VI, XII, XVI-XVIII, XXI and XXVII) showed ARI activity with IC50 ranging from 34 to 242 µM. Out of these, two compounds IV and V showed best ARI activity which is comparable with that of quercetin. As a result, two compounds (IV and V) possessing significant dual action (anti-hyperglycaemic and aldose reductase inhibition) were identified and may be used as lead compounds for developing new drugs.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Diabetes Complications/enzymology , Hypoglycemic Agents/pharmacology , Lens, Crystalline/enzymology , Pyridazines/chemistry , Sulfonylurea Compounds/pharmacology , Animals , Area Under Curve , Drug Design , Female , Male , Rats , Rats, Wistar , Spectrum Analysis/methods , Sulfonylurea Compounds/chemistry
10.
Bioorg Med Chem Lett ; 26(4): 1337-41, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26804228

ABSTRACT

A series of sulfonamide derivatives (2a-l) incorporating substituted pyridazinone moieties were investigated for the inhibition of two human cytosolic carbonic anhydrase isoforms, hCA I and hCA II. All these compounds, together with the clinically used sulfonamide acetazolamide were investigated as inhibitors of the physiologically relevant isozymes I and II. These sulfonamides showed very strong inhibition against all these isoforms with K(I)'s in the range of 0.98-8.5 nM which makes such molecules possible to be used as leads for discovery of novel effective CA inhibitors targeting other isoforms with medicinal chemistry applications.


Subject(s)
Carbonic Anhydrase Inhibitors/chemistry , Sulfonamides/chemistry , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase I/metabolism , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Drug Design , Humans , Pyridazines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Benzenesulfonamides
11.
Arch Pharm (Weinheim) ; 349(2): 150-9, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26725221

ABSTRACT

The chemistry of phthalazine derivatives has been of increasing interest since many of these compounds have found many chemotherapeutic applications. So this study aims to synthesize a library of phthalazine derivatives and to investigate their anti-inflammatory and anti-proliferative activities. Sixteen new phthalazinone derivatives (2a-p) were synthesized and tested for their in vitro antiproliferative and in vivo anti-inflammatory activities. All the synthesized compounds were identified and characterized by IR, (1) H NMR, (13) C NMR spectroscopy, and MS. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable with that of the standard drug etoricoxib in the carrageenan-induced rat paw edema model at 3 and 5 h, respectively. Three compounds (2h, 2j, and 2g) showed moderate sensitivity toward the renal cancer cell line UO-31.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antineoplastic Agents/chemistry , Phthalazines/chemistry , Sulfones/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carrageenan , Cell Line, Tumor , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Screening Assays, Antitumor , Edema/chemically induced , Edema/drug therapy , Female , Humans , Male , Phthalazines/chemical synthesis , Phthalazines/pharmacology , Rats, Wistar , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacology
12.
Bioorg Med Chem Lett ; 25(20): 4601-5, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26384286

ABSTRACT

Twenty one pyrazoline containing benzenesulfonylureas were synthesized and docked against PPAR-γ target. All the compounds were first screened for their antidiabetic potential by oral glucose tolerance test and then six active compounds were assessed on STZ diabetic model. It was found that five compounds showed significantly high antidiabetic activity in comparison to glibenclamide as well as rosiglitazone (standard drugs). The active compounds were evaluated for their effect on body weight since weight management is one of the main concerns associated with sulfonylureas. Finally, the most active compound 6f was shown to elevate PPAR-γ gene expression. The synthesized compounds were also screened for anticancer activity by National Cancer Institute. Five compounds (5i, 6e, 6g, 6i and 6j) were selected at one dose level and showed potency against cancers.


Subject(s)
Antineoplastic Agents/pharmacology , Hypoglycemic Agents/pharmacology , PPAR gamma/agonists , Sulfonylurea Compounds/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Models, Molecular , Molecular Structure , PPAR gamma/genetics , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Wistar , Streptozocin , Structure-Activity Relationship , Sulfonylurea Compounds/chemical synthesis , Sulfonylurea Compounds/chemistry
13.
Eur J Med Chem ; 95: 96-103, 2015 May 05.
Article in English | MEDLINE | ID: mdl-25800645

ABSTRACT

A series of substituted pyrazolines (2a-e, 3a-h and 6a-c) and isoxazolines (4a-e) were synthesized and their structures were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectra. All the synthesized compounds were tested against two bacterial and four fungal strains and found to exhibit moderate to potent antifungal activity. Compounds 2b, 4c, 4d and 6a-c exhibited significant activity against all tested fungal strains. MIC values of all the active compounds were comparable with standard drug fluconazole. The results of the in silico molecular docking study supported the antifungal activity of the synthesized compounds.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Bacteria/drug effects , Fungi/drug effects , Bacteria/growth & development , Cytochrome P-450 Enzyme System/chemistry , Fluconazole/pharmacology , Fungi/growth & development , Isoxazoles/chemistry , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Docking Simulation , Pyrazoles/chemistry , Structure-Activity Relationship
14.
Planta Med ; 81(5): 348-56, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25782035

ABSTRACT

The present study aimed to investigate the anti-inflammatory activity of the ethanolic extract of the aerial parts of Trichosanthes dioica and its successive fractions. The effect on oxidative stress involved in the pathogenesis of inflammation was evaluated. The ethanolic extract and its successive fractions were administered at a dose of 150 and 300 mg/kg b. w. for testing their anti-inflammatory activity by a carrageenan-induced edema model. The results showed that the ethyl acetate fraction exhibited significant potency against inflammation. Pertaining to mechanistic insight, the anti-inflammatory effect might be attributed to the attenuation in tumor necrosis factor-α level (ELISA assay) and reduced expression of cyclooxygenase-2 and nuclear transcription factor-κB (immunohistochemistry). The alleviation in oxidative stress has been pertinent to the elevation in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) by active fractions. Furthermore, the ulcerogenic effect was insignificant even at a three times higher dose. Finally, it was concluded that the ethyl acetate fraction which showed significant biological potential against inflammation and oxidative stress could be viewed as a source of effective treatment.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Inflammation/drug therapy , Oxidative Stress/drug effects , Phytotherapy , Plant Extracts/therapeutic use , Trichosanthes , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Carrageenan , Catalase/metabolism , Cyclooxygenase 2/metabolism , Edema/drug therapy , Glutathione/metabolism , Glutathione Peroxidase/metabolism , Inflammation/chemically induced , Inflammation/metabolism , Mice , NF-kappa B/metabolism , Plant Components, Aerial , Plant Extracts/pharmacology , Rats, Wistar , Superoxide Dismutase/metabolism , Tumor Necrosis Factor-alpha/metabolism
15.
Bioorg Med Chem Lett ; 24(22): 5298-303, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25442322

ABSTRACT

In the present study a library of twenty six benzenesulfonylureas containing thiophenylpyrazoline moiety has been synthesized. All the compounds were docked against PPAR-γ target. Most of the compounds displayed higher dock score than standard drugs, glibenclamide and rosiglitazone. All the synthesized compounds were primarily evaluated for their antidiabetic effect by oral glucose tolerance test. Further assessment of antidiabetic potential of sixteen active compounds was then done on STZ induced diabetic model. The results of in vivo activity by both the methods were found to be consistent with each other as well as with docking studies. Change in body weight of STZ induced animals post treatment was also assessed at the end of study. In vitro PPAR-γ transactivation assay was performed on active compounds in order to validate docking results and the most active compound 3 k was also shown to elevate gene expression of PPAR-γ. Furthermore, the compounds were screened by National Cancer Institute, Bethesda for anticancer effect and two compounds 3h and 3 i were selected at one dose level since they exhibited sensitivity towards tumor cell lines (mainly melanoma).


Subject(s)
Antineoplastic Agents/chemistry , Hypoglycemic Agents/chemistry , Pyrazoles/chemistry , Sulfonylurea Compounds/chemistry , Sulfonylurea Compounds/pharmacology , 3T3-L1 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Catalytic Domain , Cell Line , Cell Proliferation/drug effects , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Drug Screening Assays, Antitumor , Glucose Tolerance Test , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Mice , Molecular Docking Simulation , PPAR gamma/chemistry , PPAR gamma/metabolism , Rats , Rats, Wistar , Structure-Activity Relationship
16.
Bioorg Med Chem ; 22(21): 5804-12, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25311566

ABSTRACT

The present study aims at the synthesis of pyrazolines bearing benzothiazole and their evaluation as anti-inflammatory agents. The synthesized compounds were evaluated for their anti-inflammatory potential using carrageenan induced paw edema model. Two compounds 5a and 5d alleviated inflammation more than the standard drug celecoxib. Eight compounds 5 b, 5 c, 5 e, 5 g, 5 h, 6 b, 6 e and 6 f showed anti-inflammatory activity comparable to celecoxib. To understand the mode of action, COX-2 enzyme assay and TNF-α assay were carried out. All the active compounds were assessed for their cytotoxicity. The ulcerogenic risk evaluation was performed on the active compounds that were not found to be cytotoxic. Out of ten active compounds, two compounds (5 d and 6 f) were finally found to be the most potent anti-inflammatory agents attributing to the suppression of the COX-2 enzyme activity and TNF-α production without being either cytotoxic or ulcerogenic.


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Benzothiazoles/chemistry , Pyrazoles/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Binding Sites , Carrageenan/toxicity , Catalytic Domain , Celecoxib , Cell Line , Cell Survival/drug effects , Cyclooxygenase 2/metabolism , Disease Models, Animal , Edema/chemically induced , Edema/drug therapy , Edema/metabolism , Enzyme Activation/drug effects , Mice , Molecular Docking Simulation , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Tumor Necrosis Factor-alpha/chemistry , Tumor Necrosis Factor-alpha/metabolism
17.
Eur J Med Chem ; 80: 209-17, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24780598

ABSTRACT

Seventeen new pyrazoline substituted benzenesulfonylurea/thiourea derivatives (2a-q) were synthesized and characterized by elemental analysis and various spectroscopic techniques viz; IR, (1)H NMR, (13)C NMR, and MS data. Thirteen compounds showed moderate to good anti-hyperglycaemic activity in glucose fed hyperglycaemic normal rats at the dose of 0.05 mM/kg b.w. On the basis of docking results nine compounds (2a, 2c, 2e, 2h, 2k, 2l, 2n, 2o and 2q) were evaluated for their ability to inhibit rat lens aldose reductase. Out of these six compounds (2h, 2k, 2l, 2n, 2o and 2q) were found more effective than the known ARI sorbinil. Five compounds (2h, 2k, 2l, 2n and 2o) showed significant dual action (anti-hyperglycaemic and aldose reductase inhibition).


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Thiourea/chemistry , Aldehyde Reductase/chemistry , Aldehyde Reductase/metabolism , Animals , Blood Glucose/metabolism , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacology , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Conformation , Pyrazoles/chemistry , Pyrazoles/metabolism , Rats
18.
Bioorg Med Chem Lett ; 24(7): 1685-91, 2014 Apr 01.
Article in English | MEDLINE | ID: mdl-24630557

ABSTRACT

Twenty six new pyrazoline substituted benzenesulfonylureas (2a-z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k-2p, 2r, 2s-2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 µM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI50 MID) values of 2.62, 3.93, 3.33, 3.74 µM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 µM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI50 less than 2 µM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI50 less than 3 µM.


Subject(s)
Antineoplastic Agents/pharmacology , Pyrazoles/chemistry , Sulfonylurea Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Sulfonylurea Compounds/chemical synthesis , Sulfonylurea Compounds/chemistry
19.
J Enzyme Inhib Med Chem ; 29(3): 362-6, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23578313

ABSTRACT

Some new benzenesulfonylthiourea derivatives substituted with phthalazones (2a-q) were synthesized by refluxing the appropriate 4-aryl-1-oxophthalazin-2(1H)yl benzenesulfonamides with isothiocyanate in dry acetone over anhydrous K2CO3. All the synthesized compounds were characterized on the basis of IR, (1)H NMR, MS data and elemental analysis. These synthesized compounds (2a-q) at the dose of 20 mg/kg were tested for antihyperglycemic activity in the glucose-fed hyperglycemic normal rat model and among these compounds 2f and 2m showed modest antihyperglycemic activity.


Subject(s)
Benzenesulfonates/chemical synthesis , Blood Glucose/metabolism , Hyperglycemia/drug therapy , Hypoglycemic Agents/chemical synthesis , Phthalazines/chemistry , Thiourea/chemical synthesis , Animals , Benzenesulfonates/pharmacology , Drug Design , Female , Glucose/administration & dosage , Hyperglycemia/chemically induced , Hypoglycemic Agents/pharmacology , Isothiocyanates/chemistry , Male , Rats , Rats, Wistar , Structure-Activity Relationship , Thiourea/analogs & derivatives , Thiourea/pharmacology
20.
J Ethnopharmacol ; 151(2): 931-6, 2014 Feb 03.
Article in English | MEDLINE | ID: mdl-24333959

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Trapa natans L. has a folkloric reputation as nutrient, appetizer and astringent. Its utility as antidiabetic, anticancer, diuretic, aphrodisiac, antidiarrhoeal and in many other maladies is well reported in the literature. Therefore, the present study has been carried out to study the antihyperglycemic effect of root extract of Trapa natans L. and its various fractions. Furthermore, hepatotoxic effects and lipid peroxidation risks have also been evaluated. METHODS: The ethanol extract and its successive fractions obtained from roots of Trapa natans have been administered in sucrose loaded and STZ- induced diabetic Wistar rats at doses of 50, 100 and 200mg/kg b.w. Glibenclamide was used as positive control. The evaluation of protective effects of extract as well as fractions against hepatotoxicity and lipid peroxidation at 600mg/kg b.w. has also been carried out. RESULTS: The methanol fraction emerged as the most potent antihyperglycemic fraction. It has also been found that the ethanolic extract as well as its fractions did not cause any lipid peroxidation and hepatotoxicity risks. CONCLUSION: It can be concluded that the intense investigations of the methanol fraction obtained from Trapa natans root extract can be done to provide an alternative natural therapy for hyperglycemia.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Lythraceae , Plant Extracts/therapeutic use , Protective Agents/therapeutic use , Animals , Blood Glucose/analysis , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/pathology , Female , Hypoglycemic Agents/pharmacology , Lipid Peroxidation/drug effects , Liver/drug effects , Liver/pathology , Male , Mice , Phytotherapy , Plant Extracts/pharmacology , Plant Roots , Protective Agents/pharmacology , Rats , Rats, Wistar
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