hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation.

Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)-8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug-induced forms of LQTS.

A Comparative Study of the Inhibitory Action of Berberine Derivatives on the Recombinant Protein FtsZ of E. coli.

Medicinal plants belonging to the genus Berberis may be considered an interesting source of drugs to counteract the problem of antimicrobial multiresistance. The important properties associated with this genus are mainly due to the presence of berberine, an alkaloid with a benzyltetrahydroisoquinoline structure. Berberine is active against both Gram-negative and Gram-positive bacteria, influencing DNA duplication, RNA transcription, protein synthesis, and the integrity of the cell surface structure. Countless studies have shown the enhancement of these beneficial effects following the synthesis of different berberine analogues. Recently, a possible interaction between berberine derivatives and the FtsZ protein was predicted through molecular docking simulations. FtsZ is a highly conserved protein essential for the first step of cell division in bacteria. The importance of FtsZ for the growth of numerous bacterial species and its high conservation make it a perfect candidate for the development of broad-spectrum inhibitors. In this work, we investigate the inhibition mechanisms of the recombinant FtsZ of Escherichia coli by different N-arylmethyl benzodioxolethylamines as berberine simplified analogues appropriately designed to evaluate the effect of structural changes on the interaction with the enzyme. All the compounds determine the inhibition of FtsZ GTPase activity by different mechanisms. The tertiary amine 1c proved to be the best competitive inhibitor, as it causes a remarkable increase in FtsZ Km (at 40 µM) and a drastic reduction in its assembly capabilities. Moreover, a fluorescence spectroscopic analysis carried out on 1c demonstrated its strong interaction with FtsZ (Kd = 26.6 nM). The in vitro results were in agreement with docking simulation studies.

Biostimulant Formulations and Moringa oleifera Extracts to Improve Yield, Quality, and Storability of Hydroponic Lettuce.

The urgent need to increase the sustainability of crop production has pushed the agricultural sector towards the use of biostimulants based on natural products. The current work aimed to determine whether the preharvest application of two commercial formulations, based on a Fabaceae enzymatic hydrolysate or a blend of nitrogen sources including fulvic acids, and two lab-made aqueous extracts from Moringa oleifera leaves (MLEs), could improve yield, quality, and storability of lettuce grown in a hydroponic system, as compared to an untreated control. Lettuce plants treated with the MLEs showed significantly improved quality parameters (leaf number, area, and color), total phenolic content and antioxidant activity, and resistance against the fungal pathogen Botrytis cinerea, comparable to that obtained with commercial formulates, particularly those based on the protein hydrolysate. A difference between the M. oleifera extracts was observed, probably due to the different compositions. Although further large-scale trials are needed, the tested MLEs seem a promising safe and effective preharvest means to improve lettuce agronomic and quality parameters and decrease susceptibility to rots.

Microwave-Assisted Extraction of Bioactive Compounds from Lentil Wastes: Antioxidant Activity Evaluation and Metabolomic Characterization.

The recovery of industrial by-products is part of the zero-waste circular economy. Lentil seed coats are generally considered to be a waste by-product. However, this low-value by-product is rich in bioactive compounds and may be considered an eco-friendly source of health-promoting phytochemicals. For the first time, a sustainable microwave-assisted extraction technique was applied, and a solvent screening was carried out to enhance the bioactive compound content and the antioxidant activity of green and red lentil hull extracts. With respect to green lentil hull extracts that were obtained with different solvents, the aqueous extract of the red lentil seed coats showed the highest total phenolic and total flavonoid content (TPC = 28.3 ± 0.1 mg GAE/g dry weight, TFC = 1.89 ± 0.01 mg CE/100 mg dry weight, respectively), as well as the highest antioxidant activity, both in terms of the free radical scavenging activity (ABTS, 39.06 ± 0.73 mg TE/g dry weight; DPPH, IC50 = 0.39 µg/mL) and the protection of the neuroblastoma cell line (SH-SY5Y, IC50 = 10.1 ± 0.6 µg/mL), the latter of which has never been investigated so far. Furthermore, a metabolite discovery analysis was for the first time performed on the aqueous extracts of both cultivars using an HPLC separation which was coupled with an Orbitrap-based high-Resolution Mass Spectrometry technique.

Drug Repositioning for Ovarian Cancer Treatment: An Update.

Ovarian cancer (OC) is one of the most prevalent malignancies in female reproductive organs, and its 5-year survival is below 45%. Despite the advances in surgical and chemotherapeutic options, OC treatment is still a challenge, and new anticancer agents are urgently needed. Drug repositioning has gained significant attention in drug discovery, representing a smart way to identify new clinical applications for drugs whose human safety and pharmacokinetics have already been established, with great time and cost savings in pharmaceutical development endeavors. This review offers an update on the most promising drugs repurposable for OC treatment and/or prevention.

Development of Riluzole Analogs with Improved Use-Dependent Inhibition of Skeletal Muscle Sodium Channels.

Several commercially available and newly synthesized riluzole analogs were evaluated in vitro as voltage-gated skeletal muscle sodium-channel blockers. Data obtained from the patch-clamp technique demonstrated that potency is well correlated with lipophilicity and the introduction of a protonatable amino function in the benzothiazole 2-position enhances the use-dependent behavior. The most interesting compound, the 2-piperazine analog of riluzole (14), although slightly less potent than the parent compound in the patch-clamp assay as well as in an in vitro model of myotonia, showed greater use-dependent Nav1.4 blocking activity. Docking studies allowed the identification of the key interactions that 14 makes with the amino acids of the local anesthetic binding site within the pore of the channel. The reported results pave the way for the identification of novel compounds useful in the treatment of cell excitability disorders.