The cation channel Piezo1, a crucial mechanotransducer found in various organs and tissues, has gained considerable attention as a therapeutic target in recent years. Following this trend, several Piezo1 inhibitors have been discovered and studied for potential pharmacological properties. This review provides an overview of the structural and functional importance of Piezo1, as well as discussing the biological activities of Piezo1 inhibitors based on their mechanism of action. The compounds addressed include the toxin GsMTx4, Aβ peptides, certain fatty acids, ruthenium red and gadolinium, Dooku1, as well as the natural products tubeimoside I, salvianolic acid B, jatrorrhzine, and escin. The findings revealed that misexpression of Piezo1 can be associated with a number of chronic diseases, including hypertension, cancer, and hemolytic anemia. Consequently, inhibiting Piezo1 and the subsequent calcium influx can have beneficial effects on various pathological processes, as shown by many in vitro and in vivo studies. However, the development of Piezo1 inhibitors is still in its beginnings, with many opportunities and challenges remaining to be explored.

Macrocycles or medium‐sized rings offer diverse functionality and stereochemical complexity in a well‐organized ring structure, allowing them to fulfill various biochemical functions, resulting in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular compartments. These features have made macrocycles attractive candidates in organic synthesis and drug discovery. Since the 20th century, more than three‐score macrocyclic drugs, including radiopharmaceuticals, have been approved by the US Food and Drug Administration (FDA) for treating bacterial and viral infections, cancer, obesity, immunosuppression, inflammatory, and neurological disorders, managing cardiovascular diseases, diabetes, and more. This review presents 17 FDA‐approved macrocyclic drugs during the past 5 years, highlighting their importance and critical role in modern therapeutics, and the innovative synthetic approaches for the construction of these macrocycles.

Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer’s disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and β-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.

The development of novel biologically active organometallic compounds bearing an acetylsalicylic acid (ASA) substructure led to the synthesis of analogical Zeise-type salts that accordingly inhibit cyclooxygenase (COX) enzymes. In order to determine the influence of the length of the alkyl chain between the platinum(II) center and the ASA moiety, compounds with varying methylene groups (n = 1–4) were synthesized and characterized. For the propene derivative structural elucidation by X-ray crystallography was possible. Prior to evaluation of biological activity, the complexes were investigated regarding their stability in different media, such as water, physiological sodium chloride, and phosphate buffered saline. Therefore, an analytical method based on capillary electrophoresis was established. All of the compounds were tested for their COX inhibitory potential. In general, complexes with longer alkyl chains caused higher inhibition of COX enzymes and the inhibitory potential towards COX enzymes was enhanced when compared to Zeise’s salt. The growth inhibitory effects of the synthesized substances were investigated in vitro against colon carcinoma (HT-29) and breast cancer (MCF-7) cells. The IC₅₀ values of the new derivatives ranged from 30 to 50 µM, whereas neither Zeise’s salt itself nor ASA showed any antiproliferative activity at the used concentrations.

This article profiles five newly drugs containing fluorine along with fragments of amino acids or their derivatives approved by the FDA in 2024. These pharmaceuticals include Voy­deya® (danicopan), Ojemda® (tovorafenib), Itovebi® (inavolisib), Scemblix® (asciminib), and Revuforj® (revumenib). For each drug, we discuss the discovery, therapeutic areas of application, and detailed chemical synthesis.

Recent in vitro investigations of N,N′‐bis(salicylidene)‐1,2‐phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL‐60 leukemia, and cisplatin‐sensitive and ‐resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1−3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4−6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin‐1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin‐1, but even enhanced upon simultaneous application to the tumor cells.