Arginine Methyltransferase 5 (PRMT5) Inhibitors with 3-(1H-benzo[d]imidazol- 2-yl)anilines Core Identified by Virtual Screening and Biological Evaluation.

BACKGROUND: PRMT5 is a major enzyme responsible for the post-translational symmetric demethylation of protein arginine residues, which has been validated as an effective therapeutic target for cancer. Thus, many nucleoside-based PRMT5 inhibitors have been reported in the past year. OBJECTIVE: To discover a novel series of non-nucleoside PRMT5 inhibitors through a molecular docking-based virtual screening approach. METHODS: Our in-house compound library was virtually screened using the Glide program, identifying a new PRMT5 inhibitor 1. Based on the structural similarity of hit 1, a series of structure-oriented derivatives, including 3a-3e, 7a-7g, and 12a-12f, were synthesized and selected for the inhibitory activity evaluation against PRMT5, as well as cytotoxicity against MV4-11 cell. RESULTS: The analogs 7a-7e with benzimidazole core exhibited potent PRMT5 inhibitory activities, with 7e displaying the most potent activity with an IC50 of 6.81 ± 0.12 µM. In the anti-proliferative assay, compound 7e showed a strong inhibitory effect on MV4-11 cell growth. Finally, the binding mode of 7e with PRMT5 was predicted to provide insights for further structural optimization. CONCLUSION: The newly discovered PRMT5 inhibitors have potential antitumor activity against MV4-11 cells. This work highlighted this series of 3-(1H-benzo[d]imidazol-2-yl)aniline derivatives as novel anti-cancer lead compounds targeting PRMT5, which were worthy of further investigation.

Recent Advances in Antimicrobial Nano-Drug Delivery Systems.

Infectious diseases are among the major health issues of the 21st century. The substantial use of antibiotics over the years has contributed to the dissemination of multidrug resistant bacteria. According to a recent report by the World Health Organization, antibacterial (ATB) drug resistance has been one of the biggest challenges, as well as the development of effective long-term ATBs. Since pathogens quickly adapt and evolve through several strategies, regular ATBs usually may result in temporary or noneffective treatments. Therefore, the demand for new therapies methods, such as nano-drug delivery systems (NDDS), has aroused huge interest due to its potentialities to improve the drug bioavailability and targeting efficiency, including liposomes, nanoemulsions, solid lipid nanoparticles, polymeric nanoparticles, metal nanoparticles, and others. Given the relevance of this subject, this review aims to summarize the progress of recent research in antibacterial therapeutic drugs supported by nanobiotechnological tools.

Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation.

α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[b]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a, and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC50 of 26.71 ± 1.80 µM) and the positive control acarbose (IC50 of 258.53 ± 1.27 µM). Among them, compounds 8r (IC50 = 0.59 ± 0.02 µM) and 8s (IC50 = 0.65 ± 0.03 µM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC50 > 100 µM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[b]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes.

Discovery of New α-Glucosidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation.

α-Glycosidase inhibitors could inhibit the digestion of carbohydrates into glucose and promote glucose conversion, which have been used for the treatment of type 2 diabetes. In the present study, 52 candidates of α-glycosidase inhibitors were selected from commercial Specs compound library based on molecular docking-based virtual screening. Four different scaffold compounds (7, 22, 37, and 44) were identified as α-glycosidase inhibitors with IC50 values ranging from 9.99 to 35.19 µM. All these four compounds exerted better inhibitory activities than the positive control (1-deoxynojirimycin, IC50 = 52.02 µM). The fluorescence quenching study and kinetic analysis revealed that all these compounds directly bind to α-glycosidase and belonged to the noncompetitive α-glycosidase inhibitors. Then, the binding modes of these four compounds were carefully investigated. Significantly, these four compounds showed nontoxicity (IC50 > 100 µM) toward the human normal hepatocyte cell line (LO2), which indicated the potential of developing into novel candidates for type 2 diabetes treatment.

A New Endoplasmic Reticulum (ER)-Targeting Fluorescent Probe for the Imaging of Cysteine in Living Cells.

Cysteine (Cys) is an important endogenous amino acid and plays critical physiological roles in living systems. Herein, an endoplasmic reticulum (ER)-targeting fluorescent probe (FER-Cys) was designed and prepared for imaging of Cys in living cells. The probe FER-Cys consists of a fluorescein framework as the fluorescent platform, acrylate group as the response site for the selective recognition of Cys, and ER-specific p-toluenesulfonamide fragment. After the response of probe FER-Cys to Cys, a turn-on fluorescence signal at 546 nm could be detected obviously. The probe FER-Cys further shows desirable selectivity to Cys. Finally, the probe FER-Cys was proven to selectively detect Cys in live cells and successfully image the changes of Cys level in the cell models of H2O2-induced redox imbalance.

Induction of mucosal and systemic immune response by single-dose oral immunization with biodegradable microparticles containing DNA encoding HBsAg.

The purpose of this work was to assess the ability of plasmid DNA encoding hepatitis B virus (HBV) HBsAg encapsulated in poly(DL-lactide-co-glycolic acid) (PLGA) microparticles to induce local and systemic HBsAg-specific immunity following a single dose of oral immunization. RT-PCR analysis demonstrated prolonged transcription of plasmid DNA, consistent with the sustained expression and presentation of target antigen observed by confocal laser scanning microscopy, in gut-associated lymphocyte tissue (GALT) from mice immunized orally with plasmid DNA encapsulated into PLGA microparticles. Oral administration of PLGA-DNA microparticles induced a long-lasting and stable antigen-specific antibody response, both serum total antibody and intestinal IgA, in BALB/c mice. Mice immunized orally exhibited antigen-specific gamma interferon production and cytotoxic T lymphocyte responses in spleen and GALT after restimulation in vitro with HBsAg or tumour cells stably expressing HBsAg. In contrast, naked DNA vaccines given by intramuscular injection induced only systemic cellular and humoral responses to HBsAg, which were much lower than the responses elicited by oral DNA encapsulated in PLGA microparticles at equivalent doses. The results are encouraging with regard to obtaining good compliance and vaccination coverage with candidate plasmid DNA vaccines, especially in developing countries.