Rational design of thiazolidine-4-one-gallic acid hybrid derivatives as selective partial PPARγ modulators: an in-silico approach for type 2 diabetes treatment.

Type 2 diabetes mellitus is a bipolar metabolic disorder characterized by abnormalities in insulin production from ß-cells and insulin resistance. Thiazolidinediones are potent anti-diabetic agents that act through the modulation of the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor. However, their full agonistic activity leads to severe side effects by stabilizing Helix12 through strong hydrogen bonding with the TYR473 residue. Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data. To address this uncertainty and advance therapeutic options, we identified and designed a novel class of compounds (A1-A23) based on a hybrid structure combining phenolic and Thiazolidine-4-one's moieties. Our rational drug design strategy incorporated structural-activity relationship principle, and validated the docking studies through calculated the root mean square deviation. Additionally, we conducted molecular docking, binding energy, molecular dynamics simulations, and post-molecular dynamics calculations to evaluate the dynamics behavior between the ligands and protein. The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (-13.9 kcal/mol and -86.2 kcal/mol), A1 (-11.1 kcal/mol and -79.5 kcal/mol), A13 (-11.3 kcal/mol and -91.4 kcal/mol), and the co-crystal itself (-9.8 kcal/mol and -76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and ß-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein.Communicated by Ramaswamy H. Sarma.

Novel Thiazine Substituted 9-Anilinoacridines: Synthesis, Antitumour Activity and Structure Activity Relationships.

BACKGROUND: 9-anilinoacridines are acting as DNA-intercalating agents which plays an important role as antitumor drugs, due to their anti-proliferative properties. Some anticancer agents contain 9- anilinoacridines such as amsacrine (m-AMSA), and nitracrine (Ledakrine) have been already developed. METHODS: In this study, novel 9-anilinoacridines substituted with thiazines 4a-r were designed, synthesized, characterized by physical and spectral data and their cytotoxic activities against DLA cell lines were evaluated. RESULTS: Among those compounds, 4b, c, e, g, i, j, k, m, o, p, q, r exhibited significant short term in vitro cytotoxic activity against Daltons lymphoma ascites (DLA) cells with CTC50 value of 0.18 to 0.31µM. The compounds 4b, c, e, g, i, j, k, m, o, p, q, r are also exhibited significant long term in vitro anti-tumour activity against human tumor cell lines, HEp-2 (laryngeal epithelial carcinoma) by Sulforhodamine B assay with CTC50 value of 0.20 to 0.39µM. The compounds 4b, i, j exhibited significant in vivo antitumor activity with % Increase in Life Span (ILS) 48-82%. CONCLUSION: Results obtained in this study clearly demonstrated that many of the thiazine substituted 9- anilinoacridines exert interesting anti-tumour activity. The compounds 4b, i, j have significant anti-tumour activity and useful drugs after further refinement. The above derivatives will encourage to design future antitumor agents with high therapeutic potentials.

Biogenic silver nanoparticles production and characterization from native stain of Corynebacterium species and its antimicrobial activity.

In the present study, synthesis, characterization, and the antibacterial activity of silver nanoparticles from native isolate of Corynebacterium glutamicum has been reported. Silver nanoparticles were synthesized by challenging the dried biomass of C. glutamicum with aqueous diamine silver ([Ag (NH3)2]+) containing 1 mM AgNO3. Synthesized silver nanoparticles (AgNPs) were characterized by ultraviolet-visible spectroscopy and energy-dispersive X-ray (EDX) spectroscopy analysis. Morphological study of silver nanoparticles was carried out using transmission electron microscopy (TEM) and scanning electron microscope (SEM). The spherical morphology of silver nanoparticles was confirmed from SEM image. The TEM image showed the average particle size of silver nanoparticles was about 15 nm. Silver nanoparticles synthesized from C. glutamicum were found to have enhanced antimicrobial activity against selected pathogenic strains. Silver nanoparticles from pure strains of Corynebacterium species was done by many investigators, but as per the present literature, this is the first report on the production of silver nanoparticles using a native strain of Corynebacterium.