Synthesis and bio-evaluation of newer dihydropyridines and tetrahydropyridines based glycomimetic azasugars.

This study presents the synthesis and bio-evaluation of new triazolylated dihydropyridine and tetrahydropyridine azasugar scaffolds (F1-14). Azasugar glycomimetics are the synthetic substances that mimic the structural and functional characteristics of natural carbohydrates showcasing promising potential as therapeutic agents for diabetes. The α-glucosidase inhibitory activity of synthesized final compounds were evaluated against the commercially available α-glucosidase enzyme. Majority of the screened compounds displayed excellent inhibition with IC50 values ranging from 2.12 to 75.11 µM, when compared to the standard drug Acarbose. Particularly, compound F5 with IC50 value of 2.12 µM was found to be the most active compound among the series. Further molecular docking studies of selected ligands were performed to investigate the binding interactions with enzyme active sites. Their specific binding patterns have been analysed with the binding sites of Saccharomyces cerevisiae α-glucosidase. These findings suggest these candidates as the potential leads for the anti-diabetic activity.

Multispectroscopic studies of binding interaction of phosmet with bovine hemoglobin.

Phosmet is a phthalimide derived broad spectrum organophosphate pesticide which is vastly used across the globe to protect several ornamental or horticulture crops. The toxicity of phosmet is of utmost concern because of its direct effect on the nervous system of the victim after exposure. The mechanism of phosmet toxicity was explored by the interaction with the model blood protein which is hemoglobin. Bovine Hemoglobin (BHb) is a major protein of red blood cells (RBCs) that plays an important role in the exchange of gases for respiration and ensures adequate oxygen supply to tissues for oxygenation. In the current study, the interaction of BHb with phosmet was revealed using various spectroscopic techniques. Circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) studies of BHb in the presence of phosmet showed secondary structural changes in the protein post binding, Fluorescence study shows the involvement of the dynamic quenching predominantly, Van't Hoffs thermodynamic study showed negative enthalpy value and free energy change and negative entropy change that revealed the involvement of hydrogen bonding and van der Waal forces predominantly further revealing spontaneous nature of binding interaction. The shift in Ultraviolet-visible spectra also revealed the nature of the interaction. In-silico study finally deduced the involvement of hydrogen bonding and polar interaction. The study inferred the moderate interaction of BHb with phosmet.

Luminescence studies of binding affinity of vildagliptin with bovine serum albumin.

Vildagliptin (VDG)is a frontier drug for diabetes mellitus. It is prescribed both in the monotherapy as well as in an amalgamation with other antidiabetic drugs. Drug-serum protein binding is an essential parameter which influences ADME properties of the drug. In current study, binding of VDG with serum protein (bovine serum albumin: BSA) was investigated using multi-spectroscopic techniques. A computational approach was also employed to identify the binding affinity of VDG with BSA at both Sudlow I and II sites. An enzyme activity assay specific for esterase was also investigated to know the post-binding consequences of VDG with BSA. Fluorescence spectra of BSA samples treated with VDG shows static quenching with binding parameters for VDG-BSA complex show single class of equivalent binding stoichiometry(n = 1.331) and binding constant 1.1 x 104M-1 at 298.15 K. The binding constant indicates important role of non-polar interactions in the binding process. Fluorescence resonance energy transfer (FRET) analysis of VDG absorption spectra and emission spectrum of BSA confirmed no significant resonance in energy transfer. Synchronous fluorescence of BSA after binding with VDG show maximum changes in emission intensity at tryptophan (Trp) residues. Post binding with VDG, BSA conformation changes as suggested by circular dichorism (CD) spectra of BSA and this lead to enhanced protein stability as indicated by a thermal melting curve of BSA.Communicated by Ramaswamy H. Sarma.

DNA binding and antiradical potential of ethyl pyruvate: Key to the DNA radioprotection.

DNA is the store house of all necessary hereditary information for growth of cells and tissues. Physiological functionality of DNA depends on its 3D helical structure and any distortion in a structure may lead to mutation and genomic instability that may translate into disease like cancer. In order to prevent DNA damage, an exogenous compound is required that can either scavenge the excess free radicals or enhance the structural integrity of DNA through binding. In the present study, the binding mechanism of ethyl pyruvate (EP) with DNA models using different spectroscopic techniques was investigated for their structural integrity. Besides, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays were performed to determine the antioxidant scavenging of EP. Plasmid DNA relaxation assay was performed to assess the radioprotection efficacy of EP in the plasmid DNA. Circular dichroism (CD) and UV-Vis absorbance spectroscopic data confirmed the conformation change in ctDNA upon binding with EP. The molecular docking visualized that EP stacks between the DNA bases with a glide score of -2.117 kcalmol while EP binds in the minor groove region of DNA with the glide score of -1.414 kcalmol . DPPH and FRAP data confirmed that EP scavenges significantly radicals at higher concentrations. In vitro radioprotection study in plasmid DNA pBR322 showed that EP retained the supercoiled form of plasmid DNA at 50 Gy radiation dose.

Protection by ethyl pyruvate against gamma radiation induced damage in bovine serum albumin.

Environmental factors like ionizing radiation induced generation of reactive oxygen species (ROS) cause macromolecular damage under physiological conditions. Proteins are the potential targets of ROS induced oxidative damage because of their abundance and their critical functions in the biological systems. The present study investigates the protective potential of ethyl pyruvate (EP) against ionizing radiation induced oxidative damage of bovine serum albumin (BSA) using spectroscopic, biochemical and SDS-PAGE techniques. Spectroscopic data shows that EP prevents the build up of protein damage markers like bityrosine formation and oxidation of tryptophan. Protein melting studies shows that the melting temperature (Tm) of the irradiated protein does not change significantly in the presence of EP. Biochemical assays indicate that ionizing radiation causes the generation of carbonyls and malondialdehyde and the loss of thiol content in proteins that is prevented by EP. The SDS-PAGE profile of gamma irradiated BSA shows the radioprotective effect of EP. These results indicate the radiation induced oxidative and molecular changes in the protein and that the EP protected the BSA from these modifications. Therefore, these results imply that EP has a good antiradical property and hence it can be proposed as a good radioprotective agent.