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We present the design, synthesis and biophysical and biochemical evaluation of new guanidinium derivatives with potential as covalent inhibitors of Transmembrane Protease Serine 2 (TMPRSS2), aiming to find therapies against COVID-19. TMPRSS2 is a key protease for SARS-CoV-2 entry into host cells, making it a promising drug target since blocking viral entry, viral replication is stopped. We have designed five families of guanidinium derivatives with different scaffolds that would allow establishing covalent interactions with the target. The proposed structures were optimised for better binding and drug-like properties. Docking studies showed that some of the new compounds had improved binding scores over nafamostat. Physicochemical and ADME properties analysis indicated that most of the compounds exhibit favourable drug-like properties except for a small number that showed poor solubility or absorption. Different synthetic pathways were designed and optimised for the preparation of the five families, and the 40 compounds obtained were fully characterised. Unfortunately, in cell-based assays, none of the new compounds prepared effectively blocked SARS-CoV-2 entry, suggesting that further optimisation is needed. Overall, the work presented expands the chemical space for targeting TMPRSS2 and provides valuable insights for future antiviral drug development.

Pim-1, a carcinogenic threonine and serine kinase, inhibits apoptosis and advances the cell cycle. It is overexpressed in several human cancers. The proviral integration site of Moloney murine leukemia virus 1 is Pim-1. Previous studies have shown that the Pim-1 30-UTR regulates the stability of Pim-1 mRNA. Threonine and serine are identified as the proto-oncogene Pim-1 kinase. Pim-1 mediates numerous biological processes, including apoptosis, cell division, proliferation, and cancer. Pim-1-mediated anticancer activity has been reported in several analogs of thiazole/bis-thiazole, tetrazine, thiophenes, quinoline, pyrazolopyrimidine, 3-cyanopyridine, thiazolidine-2,4-dione, thieno[2,3-b]pyridine, triazolo[4,3-b]pyridazine, pyrazolo[1,5-a]pyrimidines, and pyrazolo[3,4-b]pyridine derivatives. Additionally, flavonoids and amino alcohol compounds that constitute Pim-1-mediated cancer therapy have also been identified thus far. Many compounds with Pim-1-mediated cytotoxicity have been discovered up to this point, and scientists are currently concentrating on bringing novel compounds with anticancer potential to the market.

This review provides an overview of recent advances in the development of multitarget drugs (MTDs) for cardiac diseases, with a particular focus on emerging molecular scaffolds and their pharmacological properties. We discuss the fundamental principles of cardiac polypharmacology and multitarget drug design, highlighting key compound classes, such as 1,4-benzothiazepines, 1,4-dihydropyridines (DHPs), and polyphenol derivatives. Particular emphasis is placed on the relationship between the structural features and the pharmacological activity, efficacy, and therapeutic potential of these compounds.

Neurological disorders such as Alzheimer's disease, Parkinson's disease, and neuroinflammatory conditions involve complex, interconnected mechanisms, including neuroinflammation, oxidative stress, cholinergic dysfunction, and synaptic impairment. The cannabinoid type-2 receptor (CB2R), primarily expressed in immune and glial cells, has emerged as a promising therapeutic target due to its role in modulating neuroinflammation and providing neuroprotection without the psychoactive effects associated with CB1R activation. Recent research highlights the potential of dual-acting CB2R ligands that also modulate CB1R, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), offering a multitarget approach to neurological disorders. Although CB1R expression was identified in 1993, significant progress in designing receptor modulators began in the 2000s, with recent focus expanding to autoimmune, metabolic, and cancer-related applications. This review summarizes advances in the design, synthesis, and structure–activity relationships of CB2R-targeting ligands, emphasizing dual- or multitarget agents with cholinesterase inhibitory activity. Key chemical scaffolds include synthetic cannabinoids, heterocyclic compounds, and hybrid molecules integrating cholinesterase pharmacophores. Molecular docking and in silico studies are discussed to elucidate ligand–receptor interactions, binding modes, and determinants of selectivity. Overall, CB2R-centric dual-acting ligands represent a promising strategy for addressing multifactorial neurological disorders.

We present a combined molecular simulation and experimental study of the mechanisms of calcium oxalate monohydrate formation within a biomimetic matrix. Using a double-diffusion approach to feed calcium and oxalate ions into an agarose gel, we show how selective ion association to different crystal faces may guide the morphogenesis and surface charge of the precipitates. Our analyses rationalize two conceptually different growth mechanisms leading to the aggregation of crystallites in terms of negatively charged needles and positively charged platelets, respectively, whereas embedding organic macromolecules are related to the hosting of counterions. We argue that this reflects a key characteristic of renal stone formation, while benefiting from drastic reduction of system complexity. Hence, the biomimetic setup is suggested for both, ex situ formation of (much simplified) proxies to kidney/urinary stones and steps toward the understanding of growth factors for tailoring inner structure, size, and dispersion in water.

In this study, we describe the synthesis of new 1-(1-benzyl-2-oxoindolin-3-ylidene)-4-(3-sulfamoylphenyl)thiosemicarbazides and evaluate their inhibitory activity against hCAs (6a–l). The inhibitory effects of compounds 6a–l were examined in vitro against hCA I, II, IX, and XII isoforms. Acetazolamide (AAZ) was employed as the standard reference compound in this study. The compounds 6a–l inhibited the tumor-associated hCA IX and XII isoenzymes at nanomolar levels, and showed weak inhibitory effects on the off-target hCA I and II isoenzymes. Selectivity index (SI) values of compounds 6a–l were determined to be significantly high for hCA IX and XII over hCA I and II compared to AAZ. Compound 6k (R₁ = Cl, R₂ = 3-Cl) showed the strongest inhibitory effect (K_i = 25.23 nM) and high selectivity (SI = 225, 185) against hCA IX over hCA I and II. Compound 6f (R₁ = CH₃, R₂ = 4-Cl) was found to have the highest inhibitory effect (K_i = 36.65 nM) and high selectivity (SI = 377 and 192, respectively) against hCA XII over hCA I and II. Molecular docking and dynamic simulation analyses were conducted to explore how compounds 6f and 6k interact with active sites of hCA XII and IX enzymes.

Network pharmacology (NP) is an innovative drug discovery method that provides a comprehensive view of drug–body interactions through complex biological networks. Each drug modulates specific network nodes, and understanding these interactions helps predict therapeutic effects and side effects. By integrating diverse data types and advanced computational methods, NP enables more accurate identification of new drug targets, accelerating the development of effective, targeted therapies. It also supports personalized medicine by tailoring treatments to individual biological profiles. This review examines the fundamentals and strategic significance of NP in drug discovery. Network-based approaches unravel complex molecular interactions and discover drug targets with high accuracy. Holistic NP implementation integrates omics datasets and computational tools to deliver actionable insights. The difficulty of screening all drug pairs due to time and cost constraints has driven the development of computational methods to predict side effects efficiently. NP holds transformative potential for precision medicine, promising improved patient outcomes and innovative treatments across many diseases. Conclusively, NP is transforming drug discovery by providing a whole-view approach to drug interactions and enabling effective, personalized therapeutic interventions.

Targeted protein degradation has emerged as a clinically validated therapeutic strategy, culminating in the recent FDA approval of the first proteolysis-targeting chimeras (PROTAC) drug (VEPPANU). Within PROTACs, the linker plays a central role in modulating degradation efficiency as well as physicochemical and in vitro absorption, distribution, metabolism, and excretion properties, yet linker optimization still largely relies on empirical “linkerology” approaches. Here, we investigated whether simple 2D linker descriptors could provide informative insights for very early-stage PROTAC design. Four matched PROTAC series, including both cereblon- and von Hippel–Lindau-recruiting degraders, were retrospectively analyzed using a workflow combining the in-house Bellerophon-based linker extraction with principal component analysis. Selected descriptors captured linker hydrophobicity, polarity, flexibility, and topology and were correlated with experimental degradation, permeability, solubility, lipophilicity, protein binding, and metabolic stability data. In several datasets, linker-dependent trends associated with the molecular properties of degraders and their degradation efficiency were identified, particularly for von Hippel–Lindau-based PROTACs. Although the limited size of currently available datasets prevents broad generalization, this work highlights the potential of simple descriptor-based analyses to support early candidate prioritization and reduce unnecessary synthetic efforts.

Conventional nanozymes are generally reported to have a symmetric coordination environment near the active centers that can hinder electron transfer and result in limited catalytic efficiency. In a recent article by Na Na and colleagues, an axial sulfur-bridged Mo–S–Cu (A-CuN₃S₁@MoS_2−x) nanozyme is developed that functions by utilizing an expanded asymmetric local electric field (LEF). The innovative structure significantly ramps up multienzymatic activities, which include catalase-, peroxidase-, and oxidase-like functions, while concomitantly depleting glutathione. As this nanozyme specifically targets mitochondria in tumors, it initiates a cascade of reactive oxygen species (ROS), activating combined ferroptosis and gasdermin E (GSDME)-mediated pyroptosis. We highlight these findings on how the axial-bridging strategy offers a sophisticated design for nonapoptotic tumor therapy through the modalities of coordination chemistry and electronic structure modulation.

In this work, a versatile and efficient synthetic strategy for the selective N-1 alkylation of nitro-substituted 3-haloindazoles was developed using a complex base of NaH/t-BuOK. Various alkylating agents were employed under an argon atmosphere in DMF. This method successfully yielded several N-1-alkylated indazole derivatives, including 1-benzyl-3-chloro-6-nitro-1H-indazole, 1-benzyl-3-bromo-6-nitro-1H-indazole, and related analogs, with good to excellent yields (62%–100%). Subsequent amination reactions of the 3-bromoindazole intermediates with anilines provided N-arylindazoles at the C-3 position in moderate yields (11%–70%). In parallel, Suzuki–Miyaura cross-coupling reactions with boronic acids provided direct access to arylindazoles at the C-3 position with yields ranging from 54% to 92%. Of the compounds evaluated biologically, 16 and 18c stand out, having shown high inhibition of CDK2 (100% at 10 μM), while 13e and 16 showed maximum inhibition of ERK2 (100% at 10 μM), both proteins implicated in cancer.