N-Hydroxyalkanamide Based Organo/hydrogels as Novel Scaffolds for pH-Dependent Metronidazole and Theophylline Release.

The traditional delivery of metronidazole and theophylline presents challenges like bitter taste, variable absorption, and side effects. However, gel-based systems offer advantages including enhanced targeted drug delivery, minimized side effects, and improved patient compliance, effectively addressing these challenges. Consequently, a cost-effective synthesis of N-hydroxyalkanamide gelators with varying alkyl chain lengths was achieved in a single-step reaction procedure. These gelators formed self-assembled aggregates in DMSO/water solvent system, resulting in organo/hydrogels at a minimum gelation concentration of 1.5 % w/v. Subsequently, metronidazole and theophylline were encapsulated within the gel core and released through gel-to-sol transition triggered by pH variation at 37 °C, while maintaining the structural-activity relationship. UV-vis spectroscopy was employed to observe the drug release behavior. Furthermore, in vitro cytotoxicity assays revealed cytotoxic effects against A549 lung adenocarcinoma cells, indicating anti-proliferative activity against human lung cancer cells. Specifically, the gel containing theophylline (16HAD+Th) exhibited cytotoxicity on cancerous A549 cells with IC50 values of 19.23±0.6 µg/mL, followed by the gel containing metronidazole (16HAD+Mz) with IC50 values of 23.75±0.7 µg/mL. Moreover, the system demonstrated comparable antibacterial activity against both gram-negative (E. coli) and gram-positive bacteria (S. aureus).

1,2,3-Triazole-based esters and carboxylic acids as nonclassical carbonic anhydrase inhibitors capable of cathepsin B inhibition.

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a KI value of 0.7 µM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10-7 M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC50 values lower than 100 µM.

Endocytosis of LXRs: Signaling in liver and disease.

Nuclear receptors are among one of the major transcriptional factors that induces gene regulation in the nucleus. Liver X receptor (LXR) is a transcription factor which regulates essential lipid homeostasis in the body including fatty acid, cholesterol and phospholipid synthesis. Liver X receptor-retinoid X receptor (LXR-RXR) heterodimer is activated by either of the ligand binding on LXR or RXR. The promoter region of the gene which is targeted by LXR is bound to the response element of LXR. The activators bind to the heterodimer once the corepressor is dissociated. The cellular process such as endocytosis aids in intracellular trafficking and endosomal formation in transportation of molecules for essential signaling within the cell. LXR isotypes play a crucial role in maintaining lipid homeostasis by regulating the level of cholesterol. In the liver, the deficiency of LXRα can alter the normal physiological conditions depicting the symptoms of various cardiovascular and liver diseases. LXR can degrade low density lipoprotein receptors (LDLR) by the signaling of LXR-IDOL through endocytic trafficking in lipoprotein uptake. Various gene expressions associated with cholesterol level and lipid synthesis are regulated by LXR transcription factor. With its known diversified ligand binding, LXR is capable of regulating expression of various specific genes responsible for the progression of autoimmune diseases. The agonists and antagonists of LXR stand to be an important factor in transcription of the ABC family, essential for high density lipoprotein (HDL) formation. Endocytosis and signaling mechanism of the LXR family is broad and complex despite their involvement in cellular growth and proliferation. Here in this chapter, we aimed to emphasize the master regulation of LXR activation, regulators, and their implications in various metabolic activities especially in lipid homeostasis. Furthermore, we also briefed the significant role of LXR endocytosis in T cell immune regulation and a variety of human diseases including cardiovascular and neuroadaptive.