Neha Rahuja

Synthesis and antihyperglycemic activity of phenolic C-glycosides.

Various phenolic C-glycosides were evaluated for their in vitro and in vivo antihyperglycemic activity employing glucose uptake by rat muscle cell lines (L-6) and low dosed-streptozotocin-induced diabetic rats, respectively. Some of phenolic C-glycosides were isolated from Pterocarpus marsupium and Ulmus wallichiana and other were synthesized by unprotected sugar and phloroacetophenone using Sc(OTf)(3) in aqueous ethanol. Eight among tested compounds showed significant lowering of blood glucose level on low dosed-streptozotocin-induced diabetic rats. The compound 24 lowered the blood glucose levels by 34.9% and 33.6% during 0-5h and 0-24h, respectively, at the dose of 25mg/kg body weight which is comparable to standard antidiabetic drug metformin.

Synthetic studies in butenonyl C-glycosides: Preparation of polyfunctional alkanonyl glycosides and their enzyme inhibitory activity

A simple synthesis of phenyl butenoyl C-glycosides has been achieved by Aldol condensation of peracetylated glycosyl acetones with aromatic aldehydes followed by deacetylation with methanolic NaOMe. The selected butenoyl C-glycosides on conjugate addition of diethyl malonate resulted in polyfunctional alkanonyl glycosides in good yields. The butenoyl C- and alkanoyl C-glycosides were evaluated for their alpha-glucosidase, glucose-6-phosphatse and glycogen phosphorylase enzyme inhibitory activities in vitro. Three of the synthesized (3, 5 and 9) showed potent enzyme inhibitory activities as compared to standard drugs. Compounds 3, 5 and 9 were evaluated in vivo too displaying significant activity as compared to standard drugs acarbose and metformin.

Synthesis of novel triterpene and N-allylated/N-alkylated niacin hybrids as α-glucosidase inhibitors

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia. α-Glucosidase (EC 3.2.1.20) inhibitors interfere with enzymatic action to slow down the liberation of d-glucose from oligosaccharides and disaccharides, resulting in delayed glucose absorption and decreased postprandial plasma glucose levels. In continuation of our drug discovery program on antidiabetic agents, we synthesized novel N-allylated/N-alkylated niacin and α-amyrin (4-9) and lupeol (12-16) hybrids and tested for their α-glucosidase inhibiting activity. Compounds 4-9 showed better activity profile than the marketed α-glucosidase inhibitor i.e. acarbose. Compound 4 possess the highest inhibitory action with IC50 of 5 μM. Kinetic and CD studies revealed that 4 inhibited the α-glucosidase in a noncompetitive manner and caused conformational changes in secondary structure of the enzyme protein.

Synthesis and antihyperglycemic evaluation of new 2,4-thiazolidinediones having biodynamic aryl sulfonylurea moieties

New 2,4-thiazolidinediones with aryl sulfonylurea moieties have been synthesized by condensing various substituted sulfonamides and 5-(isocyanatomethyl) thiazolidino-2,4-dione. The isocyanomethyl thiazolidinedione was obtained by using the Curtius rearrangement, starting from known 2,4-dioxo-5-thiazolidineacetic acid. The newly synthesized compounds have been evaluated for the antihyperglycemic activity in normal rats model and among these compounds showed significant antihyperglycemic activity in sucrose loaded rat model.

Antihyperglycemic activity of phenylpropanoyl esters of catechol glycoside and its dimers from Dodecadenia grandiflora

Bioactivity-guided separation of an antihyperglycemic extract from the leaves of Dodecadenia grandiflora afforded two phenylpropanoyl esters of catechol glycosides (1 and 4) and two lignane bis(catecol glycoside)esters (2 and 3). Their structures were established on the basis of extensive spectroscopic analysis (1D and 2D-NMR, MS). Compounds 2 and 3 are believed to be derived from dimerization via the two phenylpropanoid units of 1. Compounds 1-4 showed significant antihyperglycemic activity in streptozotocin-induced (STZ) diabetic rats, which is comparable to the standard drug metformin. Our results provide support to explain the use of D. grandiflora as antihyperglycemic agent by the traditional medical practitioners.

A convenient synthesis of novel pyranosyl homo-C-nucleosides and their antidiabetic activities

A series of pyranosyl homo-C-nucleosides have been synthesized by reaction of butenonyl C-glycosides (5a-5j, and 8) and cyanoacetamide in presence of t-BuOK followed by further modifications. The reaction proceeds by Michael addition of cyanoacetamide to the butenonyl C-glycosides and subsequent dehydrative cyclization and oxidative aromatization to give glycosylmethyl pyridones (6a-6j, 7a-7j, 9, and 10). The glycosylmethyl pyridones (6a-6e) on reaction with POCl(3) under reflux gave respective glycosylmethyl pyridines (11a-11e and 12a-12e) in good yields. The synthesized compounds were screened for their in vitro α-glucosidase, glucose-6-phosphatase and glycogen phosphorylase inhibitory activities. One of the pyridylmethyl homo-C-nucleoside, compound 11d, displayed 52% inhibition of glucose-6-phosphatase as compared to the standard drug sodium orthovanadate while compound 12a showed a significant antihyperglycemic effect of 17.1% in the diabetic rats as compared to the standard drug metformin.

Identification of novel PTP1B inhibitors by pharmacophore based virtual screening, scaffold hopping and docking.

Design and synthesis of protein tyrosine phosphatases-1B (PTP1B) inhibitors are important for the drugs targeted to treat diabetes and obesity. The pharmacophore modeling, docking and scaffold hopping techniques have been applied to discover the novel PTP1B inhibitors. The ten prioritized compounds (115-119, 120-121, 127, 130-131) from the library of 86 compounds were synthesized and found positive in the micro molar range for PTP1B in-vitro inhibitory assays as compared to Suramin (IC50 9.5 μM). Among these five active compounds (115-119) were tested in STZ-s induced diabetic rat model and the most active compound 115 in this test, was further tested in C57BL/KsJ-db/db mice where it significantly improved OGTT along with the fasting and random blood glucose level. The treatment by the compound 115 significantly improved the insulin resistance and insulin signaling by restoring the insulin level and normalizing the serum lipid profile. Compound 115 also augmented the insulin action by modulating the expression of genes involved in insulin signaling like IRS 1-2, PI3K, PTPN1, Akt2, AMPK and PPAR-α. Western blot analysis of both skeletal muscle and liver demonstrated that proteins and intermediate enzymes of insulin signaling were also increased as compared to control group. The compound 115 was also investigated for anti-adipogenic effect on 3T3L-1 cells. The compound 115 inhibited MDI induced lipid accumulation in a dose-dependent manner. The oral bioavailability of compound 115 was ∼10.29% after 30 mg/kg oral dosing assessed in rat.

Synthesis, structure-activity relationship and docking studies of substituted aryl thiazolyl phenylsulfonamides as potential protein tyrosine phosphatase 1B inhibitors.

Type 2 diabetes mellitus (T2DM) is a growing chronic diseases both in developed and developing countries. It is a metabolic disorder characterized by insulin resistance and hyperglycemia. If left untreated, the hyperglycemia and associated dyslipidemia lead to long-term problems such as retinopathy, nephropathy and neuropathy. Though a large number of antidiabetic agents are available for the treatment of diabetes, the number of individuals with diabetes worldwide has increased from 30 million in 1985 to at least 180 million people in 2000, and this number is likely to double by 2030 according to a recent World Health Organization (WHO) report. As such, there are increasing research efforts to identify novel targets and new chemical entities (NCEs) to combat this problem. Protein tyrosine phosphatase 1B (PTP1B) is a typical member of protein tyrosine phosphatase superfamily, and its inhibition results both in increased insulin sensitivity and resistance to obesity, with no abnormalities in growth or fertility or other pathogenetic effects. 4] Hence, PTP1B is considered to be an excellent target for the treatment of type 2 diabetes and obesity. Efforts are being made to discover orally active and selective PTP1B inhibitors that could be useful for probing signal transduction pathways as well as for the treatment of diabetes and obesity. Several active PTP1B inhibitors reported in recent years include difluoromethylene phosphonate (DFMP) pTyr mimetics, arylketone DFMP, benzotriazole DFMP, naphthyl DFMP, dicarboxylic acid-containing O-malonyltyrosine (OMT) and ocarboxy-(O-carboxymethyl)tyrosine peptide, benzoic acid derivatives, hydroxypropionic acid pTyr mimetics, dicarboxylic acid-containing thiophene scaffolds, thiadiazolidinedione (TDZ) and thiazolidinediones scaffolds, unsaturated isothiazolidin-3(2H)-one 1,1-dioxide and saturated isothiazolidin-3-one 1,1-dioxide (IZD) pTyr mimetics, sulfonamidebenzimidazoles, aryl trifluoromethyl sulfones, aryl trifluoromethyl sulfonamide pTyr mimetics, aryl sulfamic acids, and 2-arylsulfonylaminobenzothiazoles (for structures, see Figure S6 in the Supporting Information). Most of the inhibitors containing multiple charged phosphate mimicking components cannot be developed into effective drugs because of their low cell permeability and bioavailability. In view of the above and considering the present PTP1B inhibitors with different scaffolds, a series of 28 aryl thiazolyl phenylsulfonamides was synthesized and screened for PTP1B inhibitory activity (Table 1). The design of these molecules was based on the observation that the sulfonyl moiety in different scaffolds, such as aryl trifluoromethyl sulfone and aryl trifluoromethyl sulfonamide pTyr mimetics and arylsulfamic acid, interacts with the catalytic A site (Ile 221, Ala 217, Gln 262), the non-catalytic B site (Arg 254, Arg 24, Tyr 20), and the C site (Arg 47, Asp 48, Phe 182). In addition, sulfonamides are known to function as good hydrogen acceptors in biological systems. Using a fragment-based approach, compounds containing a sulfonyl moiety were designed, synthesized and evaluated for their in vitro PTP1B inhibitory and in vivo antidiabetic (STZ model) activities. Since the synthesized compounds show promising PTP1B inhibitory activity, docking simulations of selected compounds were also performed to analyze the potential binding mode of these compounds. The results of these studies are presented herein. The compounds were synthesized from the cyclized intermediates according to a literature procedure. Substituted (R) aniline, on reaction with benzoyl isothiocyanate in dry benzene, results in the formation of phenylcarbamothioyl benzamides 1, which upon alkaline hydrolysis give corresponding thioureas 2. Condensation of the phenylthiourea with 2-bromoethylamine in the presence of hydrogen bromide affords 4,5-dihydrothiazol-2-amines 3, which on reaction with substituted (R) benzene sulfonyl chlorides give the desired compounds 4–6 (Scheme 1). The synthesis of compound 6 a from N-(2-(trifluoromethyl))-4, 5-dihydrothiazol-2-amine (3 c) is given in the Experimental Section; details of all intermediate and final compounds are given in the Supporting Information. In order to fully explore the structure–activity relationships associated with the PTP1B inhibitors, we sought to probe hydrophobic, steric and electronic requirements by efficiently and systematically installing R and R substituents on the core aryl thiazolyl phenylsulfonamide scaffold. A series of 28 substituted aryl thiazolyl phenylsulfonamides was synthesized and evaluated against PTP1B using a colorimetric, non-radioactive PTP1B assay (Table 1). Among these, the most active compound 6 a with a 2-trifluoromethyl group at R and a 4-methoxyphenyl group at R showed good in vitro inhibitory activi[a] K. Varshney, S. Gupta, N. Singh, Dr. A. K. Saxena Division of Medicinal and Process Chemistry Council of Scientific and Industrial Research (CSIR) Central Drug Research Institute (CDRI) Chattar Manzil Palace, M G Marg, Lucknow, Uttar Pardesh 226001 (India) E-mail : anilsak@gmail.com [b] N. Rahuja, A. K. Rawat, Dr. A. K. Tamarkar, Dr. A. K. Srivastava Division of Biochemistry, CSIR–CDRI Lucknow, Uttar Pardesh 226001 (India) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201200197.

Nymphaea rubra Ameliorates TNF-α-Induced Insulin Resistance via Suppression of c-Jun NH2-Terminal Kinase and Nuclear Factor-κB in the Rat Skeletal Muscle Cells

In this work, we demonstrated insulin signaling and the anti-inflammatory effects by the chloroform fraction of ethanolic extract of Nymphaea rubra flowers in TNF-α-induced insulin resistance in the rat skeletal muscle cell line (L6 myotubes) to dissect out its anti-hyperglycemic mechanism. N. rubra enhances the GLUT4-mediated glucose transport in a dose dependent manner and also increases the tyrosine phosphorylation of both IR-β and IRS-1, and the IRS-1 associated PI-3 kinase activity in TNF-α-treated L6 myotubes. Moreover, N. rubra decreases Ser307 phosphorylation of IRS-1 by the suppression of JNK and NF-κB activation. In conclusion, N. rubra reverses the insulin resistance by the inhibition of c-Jun NH2-Terminal Kinase and Nuclear-κB.

Design, synthesis and docking studies on phenoxy-3-piperazin-1-yl-propan-2-ol derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of substituted phenoxy-3-piperazin-1-yl-propan-2-ols has been synthesized and evaluated for PTP1B inhibitory activity in vitro and for antidiabetic activity in vivo. Two molecules viz. 4a and 5b showed PTP1B inhibition of 31.58% and 35.90% at 100 μM concentration. The compound 4a also showed 40.3% normalization of plasma glucose levels at 100mg/kg in Sugar-loaded model (SLM) and 32% activity in Streptozodocin model (STZ). The docking studies of these molecules revealed that hydrogen bond formation with Arg221 is important for activity.