Synthesis, biological evaluation and in silico and in vitro mode-of-action analysis of novel dihydropyrimidones targeting PPAR-gamma

Hepatocellular carcinoma, a fatal liver cancer, affects 600 000 people annually and ranks third in cancer-related lethality. In this work we report the synthesis and related biological activity of novel dihydropyrimidones. Among the tested compounds, 5-acetyl-4-(1H-indol- 3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4g) was found to be most active towards the HepG2 cell line (IC50 = 17.9 mu M), being at the same time 7.6-fold selective over normal (LO2) liver cells (IC50 = 136.9 mu M). Subsequently, we identified peroxisome proliferator-activated receptor gamma as a target of compound 4g using an in silico approach, and confirmed this mode-of-action experimentally

Synthesis, Computational Studies, and Anti-Tuberculosis Activity of Benzoxazines That Act as RAGE Inhibitors

Peer reviewed: TrueFunder: Government of KarnatakaNovel benzoxazines were synthesized by microwave irradiation and tested for their potential binding affinity towards receptors of advanced glycation end products (RAGE). We found that the compound (2-(2-bromophenyl)-6-methyl-2,4-dihydro-1H-benzo[d][1,3]oxazine) (3i) is a lead inhibitor of RAGE. Further, our in silico prediction that benzoxazines dock towards the AGE binding region of RAGE suggests that these ligands could bind effectively at the hydrophobic pocket of the receptor and additionally form key interactions with Arg48 and Arg104, revealing its diversity in developing anti-RAGE drugs to treat AGE–RAGE-dominant disease conditions. Functionally, we herein report the anti-tuberculosis activity of small molecules which could be bioactive in the culture of mycobacterium tuberculosis

Synthesis, glycosidase inhibitory activity and computational studies of dideoxymethylnojirimycin and its derivatives

We report here the synthesis and biological evaluation of dideoxynojirimycin and its analogs and their functional effect on glucosidase enzyme inhibition against α-glucosidase(yeast), α-galactosidase and β-galactosidase (kluyveromyces lactis). All the compounds significantly inhibited the α-glucosidase(yeast) activity when compared to DNJ and shown strong inhibition against β-galactosidase (kluyveromyces lactis) when compared to DNJ. The molecular docking studies also reveals that these compounds showing strong ligand binding energies against yeast-ɑ-glucosidase- I, yeast β-galactosidase and human lysosomal acid–ɑ-glucosidase. Interestingly the analogues having N-H, N-alkyl and N-benzyl group along with ethyl group significantly inhibited the β-galactosidase activity when compared to DNJ. The in-silico studies are in correlation with invitro activity data; therefore, this study will be useful to develop further glycosidase inhibitors

Electrocatalytical properties of Au(111-25nm) - Pd quasi-single crystal film electrodes as probed by ATR-SEIRAS

Electrochemical and electrocatalytic properties of thin films Au(111-25 nm), which are quasi-single-crystal electrodes 25 nm thick made of gold with the (I 11) preferential orientation, and same electrodes modified with a monolayer (ML) of palladium are studied in 0.1 M solutions of HClO4 and H2SO4 employing voltammetric techniques and surface enhanced infrared reflection absorption spectroscopy (ATR-SEIRAS). Spectroscopic experiments demonstrate strong adsorption of electrolyte species (H2O, OHads, anions) on the Pd surface. The weak and reversible adsorption of CO on Au(111-25 nm) does not change the interfacial-water structure. Adsorption of CO on the Pd-modified film results in an irreversibly adsorbed CO adlayer stabilized by co-adsorbed isolated water species. Various electrooxidation mechanisms are discussed. Electrochemical and spectroscopic investigations on the adsorption and electrooxidation of HCOOH on bare and I ML Pd-Au(111-25 nm) electrodes reveal that electrooxidation proceeds in both cases via a direct or dehydrogenation pathway. This mechanism involves the formation of formate as intermediate, which is detected by in situ ATR-SEIRAS. The reactivity on Pd-modified surfaces is higher than on bare gold. The specifically adsorbed anions (sulfate/bisulfate) and the oxide formation on the substrate surface lower the reactivity for CO and HCOOH on both surfaces

<i>In vitro</i> effect of compound 7 and its synergistic effect with acarbose on rat intestinal maltase and sucrase activities.

<p>Percentage inhibition of compound 7 on intestinal (A) maltase and (B) sucrose. Percentage inhibition of intestinal maltase (C) and sucrase (D) induced by the compound 7 in presence of acarbose. Percentage inhibition is presented as mean ± SEM of three independent experiments. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 significant compared to acarbose.</p

General procedure for the synthesis of novel benzoxazines.

<p>General procedure for the synthesis of novel benzoxazines.</p

Effect of compound 7 on glucose transport across porcine diaphragm in the presence and absence of insulin.

<p>Values are presented as presented as mean ± SEM of three independent experiments. ***<i>p</i><0.001 significant compared to insulin alone treated diapharagm.</p

Interaction map of MGAM-C catalytic domain co-crystallized with Compound 7.

<p>The labelled key amino acids are represented as a stick model with carbon atom as green, and other atoms with their parent colour. The binding of compound 7, whose carbon atom is coloured in pink and other atoms with their parent colour. The hydrogen bonding is represented in dark dotted line.</p