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Alzheimer's disease (AD) is a multifactorial neurodegenerative disease with manifold underlying pathophysiological mechanisms. Therefore, multitarget-directed ligands potentially offer beneficial therapeutic effects compared with classical therapies. Dual targeting of the histamine H₃ receptor (H₃R) and acetylcholinesterase (AChE) is a valid strategy for the treatment of AD. In this work, a new series of pyrrolo[2,3-d]pyrimidines fused to fluorobenzylpiperidine derivatives was designed, synthesized, and pharmacologically evaluated. Among the 16 derivatives reported here, compounds 4a (IC₅₀ = 2.19 µM for human acetylcholinesterase (hAChE) and K_i = 1.05 µM for H₃R) and 4f (IC₅₀ = 4.27 µM for hAChE and K_i = 1.31 µM for H₃R) show the most balanced dual targeting behavior coupled with moderate affinities at both targets. Selected compounds showed medium inhibition of butyrylcholinesterase (BuChE). Moreover, these compounds did not show any toxicity in the SH-SY5Y or HEK-293 cell lines at pharmacologically relevant concentrations. In silico studies allowed the proposition of binding modes and the prediction of favorable absorption, distribution, metabolism and excretion properties. The cumulative results suggest compounds 4a and 4f as lead structures for the further development of novel dual-targeted ligands for AD therapy.

Acinetobacter baumannii is one of the major causes of severe hospital- and community-acquired infections, posing a significant threat to human lives. A. baumannii has already generated resistance to almost all of the currently available antibiotics, but no new class of antibacterials have been launched for the treatment of infections caused by A. baumannii in the last half century, creating an urgent need to develop novel antibacterials. Azoles as a broad class of five-membered nitrogen-containing aromatic heterocycles are privileged pharmacophores widely found in pharmaceuticals. Azoles could target on diverse enzymes, proteins, and receptors in A. baumannii via various noncovalent interactions. Particularly, azole hybrids have potential advantages in increasing therapeutic efficacy and circumventing drug resistance, representing useful scaffolds for the discovery of novel anti-A. baumannii agents. This review outlines the current scenario of the antibacterial therapeutic potential of azole hybrids against A. baumannii, developed from 2020 onwards, aiming to provide potential candidates for further preclinical/clinical evaluations and facilitate the rational design of more effective candidates.

Hyperactivation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Based on a previously reported lead compound, iCRT14, a series of 2,4-thiazolidinedione derivatives were designed, synthesized, and evaluated in vitro for their antiproliferative activity against colon cancer cells. Compound 15k exhibited the most potent activity against the HCT116 and SW480 cell lines. Compound 15k inhibited Wnt/β-catenin signaling by disrupting the protein–protein interactions between β-catenin and TCF4. Compound 15k simultaneously inhibited tubulin polymerization, disorganized the microtubule network, and arrested the cell cycle at the G2/M phase, offering an additional mechanism of action and 15k induced cell apoptosis by activating caspase-3 and poly(ADP-ribose) polymerase. Additionally, compound 15k inhibited cell migration without affecting the levels of β-catenin protein. These results offer guidance for developing the current series as potential new anticancer therapeutics.

Quantitative proteomics, an integral subfield within proteomics, is pivotal for elucidating complex biological processes. By integrating with other omics data, quantitative proteomics facilitates system-level analysis and significantly advances our understanding of cellular networks and disease mechanisms. The ongoing advancements in quantitative proteomics technology significantly boost its importance by improving analytical accuracy. This review focuses on quantitative proteomics employing liquid chromatography-mass spectrometry (LC-MS), a cornerstone technique renowned for its sensitivity, selectivity, accuracy, and throughput. The efficacy of LC-MS proteomics is heavily reliant on sample preparation, which encompasses protein extraction, total protein estimation, reduction, alkylation, digestion, and cleanup. For the very first time, this article provides a detailed examination of sample preparation methods offering insights and guidelines that researchers can utilize to refine their experimental protocols which were not critically evaluated before. By optimizing sample preparation workflows, researchers can enhance the robustness and reproducibility of their proteomic studies. By understanding the complexities of sample preparation in quantitative proteomics, researchers can optimize their experimental workflow to improve the robustness and reproducibility of their results. This review provides a comprehensive overview of sample preparation strategies in quantitative proteomics using LC-MS, discussing the underlying principles and key considerations for each step. By delving into the complexities of sample preparation, this article aims to aid researchers in optimizing their workflows to achieve robust and reproducible results, which ultimately drive innovations and breakthroughs in biomedical research and healthcare.

Cardiovascular diseases (CVDs), the leading cause of human death worldwide, are diseases that affect the heart and blood vessels and include arrhythmias, coronary atherosclerotic heart disease, hypertension, and so on. Resveratrol (RSV) is a natural nonflavonoid phenolic compound with antioxidant, anti-inflammatory, anticancer, and cardiovascular protection functions. RSV has shown significant protective effects against CVD. However, RSV's clinical application is limited by its tendency to be oxidized and metabolized easily. Therefore, it is necessary to optimize the RSV structure. This review will introduce the activity, synthesis, and structure–activity relationships of RSV derivatives, and the mechanism of the action of RSV in CVDs in recent years.

Yellow fever (YF) is a mosquito-borne virus with high mortality rates, affecting regions in South America and Africa. Despite the effectiveness of YF vaccines, increased global demand and reports of rare, severe side effects have spurred the search for safer therapeutic alternatives. Current treatments lack specific antiviral drugs approved for YF, underscoring the need for new, effective therapies. This study investigated the potential of Passiflora edulis f. edulis leaf and stem extracts as antiviral agents against the yellow fever virus (YFV). In vitro tests showed that the extracts significantly reduced YFV viral loads by twofold in Huh-7 cells and 1.5-fold in Vero-h-Slam cells at a concentration of 50 µg/mL, with a smaller reduction at 25 µg/mL and no cytotoxic effects on either cell line. Phytochemical analysis identified a new C-deoxyhexosyl flavone, luteolin-8-(1-C-β-boivinopyranosyl)-4′1-O-β-d-glucopyranoside, along with several known compounds. Protein–protein interaction (PPI) network analysis using the STRING database and Cytoscape software revealed key hub genes, including IFNA1, IL7R, CD19, IL2RA, and IFNG, crucial in antiviral defense. Molecular docking studies further evaluated how these compounds interact with the YFV NS2B-NS3 protease, essential for viral replication. Molecular dynamics (MD) simulations confirmed the stability of these interactions over a 120-nanosecond period, supporting the compounds’ antiviral potential. This study demonstrates the promise of Passiflora edulis metabolites as a foundation for developing novel YFV therapies by combining computational and experimental insights.

The development of novel cholesterol biosynthesis inhibitors is a task of major concern due to the diverse roles of cholesterol and its precursors in physiological processes. Therefore, appropriate screening assays are required, which can be used to identify and quantify specific inhibitors targeting the desired enzyme. Here, we developed a whole-cell screening assay based on a HL60 cell line, which can be used to characterize inhibitors interacting with enzymes of the isoprenoid part of cholesterol biosynthesis. Due to the change of the isoprenoid pattern under enzyme inhibition, an identification of the targeted enzyme is possible. With the described assay, we can distinguish between free and pyrophosphorylated isoprenoids after enzymatic cleavage in cellular and extracellular matrices. The approach was validated in line with the European Medicines Agency guideline on bioanalytical method validation. As proof of concept, literature-described inhibitors of the isoprenoid pathway were tested. We characterized the effect of 11 isoprenoid biosynthesis inhibitors, and we identified 6-fluoromevalonate as an isopentenyl pyrophosphate isomerase inhibitor, a biological activity that was previously unknown. Furthermore, isoprenoid patterns revealed that, independent of the analyzed matrix, the predominant form of the detected isoprenoids were dephosphorylated isoprenoids and only small amounts were present as pyrophosphates.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairments and is considered the most prevalent form of dementia. Among the contributing factors to AD lies the hyperphosphorylation of the microtubule-associated protein tau. Phosphorylated tau reduces its affinity for microtubules and triggers other posttranslational modifications that result in its aggregation and assembly into filaments. These structures progressively accumulate within neurons leading to neurodegeneration. While current AD medications often involve undesirable side effects, the exploration of natural products as a potential therapeutic alternative has gained considerable attention. Numerous compounds have shown potential capacity for reducing tau pathology through different mechanisms, such as inhibiting kinases to reduce tau hyperphosphorylation, enhancing phosphatase activity, and blocking fibril formation. Since tau hyperphosphorylation-induced aggregation is pivotal in AD onset, this review aims to elucidate the potential of natural products in modulating this crucial molecular mechanism.