Archiv der Pharmazie最新文献

Cancer, as a fatal metastatic disease, exerts a deep-seated and extensive influence on human health, impacting not just the physical condition of patients but also their psychological state and social lives. Hydroxamic acid derivatives, as exceptional histone deacetylase (HDAC) inhibitors, could regulate diverse cellular pathways, cause cell cycle arrest, and promote programmed cell death. Consequently, hydroxamic acid derivatives demonstrate significant efficacy in combating a wide range of cancers, including hematological malignancies and solid tumors. Moreover, diverse hydroxamic acid derivatives have already been applied in clinics or are currently undergoing clinical trials for cancer therapy, revealing that hydroxamic acid derivatives hold great promise as scaffolds for exploring novel anticancer agents. This review aims to comprehensively summarize the current scenario of hydroxamic acid derivatives with in vivo antitumor therapeutic potential, along with their metabolic profiles, pharmacokinetic properties, toxicity, and mechanisms of action, developed since 2020, to facilitate further rational design of safer and more potent candidates.

The β-carboline hybrids represent innovative therapeutics for Alzheimer's disease (AD) as multitarget-directed ligands (MTDLs), addressing cholinergic deficits through AChE/BuChE inhibition, amyloid-β (Aβ) aggregation, tau hyperphosphorylation via GSK-3β/DYRK1A suppression, neuroinflammation and oxidative stress. Structure–activity relationships (SARs) indicate that fluorine enhances BuChE selectivity through Tyr128 hydrogen bonding, hydrophobic extensions (α-naphthyl substituted β-carboline) optimise Aβ disaggregation and C4-8 spacers (piperazine-linked bivalent β-carboline) facilitate dual-target engagement without compromising blood–brain barrier permeability. Validated pharmacophore models prioritise planar cores for π–stacking, cationic centres for AChE/NMDA targeting and flexible linkers, positioning these hybrids as clinically translatable, disease-modifying candidates. In this extensive review, we summarised the derivatives and hybrids of carboline over the past decade for managing AD. We focus on their design, pharmacological activity and SAR analysis, as well as an exclusive pharmacophore model for both single- and multitarget carboline derivatives. We hope this review enhances the reader's understanding of future exploratory options for carboline hybrids in AD management.

Acute hepatic injury (AHI) is a sudden onset of hepatic inflammation, a key contributor to the progression of diabetes and other disorders. Diabetes mellitus also increases the risk of liver illnesses associated with inflammatory disorders. According to recent studies, Saroglitazar (SAR), originally developed for the treatment of hyperglycemia and dyslipidemia, has also demonstrated notable anti-inflammatory properties. In our search for a prime therapeutic approach for inflammatory liver disorders in diabetic patients, we investigated the effects of SAR on thioacetamide (TAA)-induced AHI in rats. In order to investigate possible interactions between SAR and thioredoxin-interacting protein (TXNIP), this research utilized a multistep methodology that included prediction of computational targets, network analysis, molecular docking, and experimental verification. Findings revealed the anti-inflammatory potential of SAR, presumably ascribed to its inhibition of the NLRP3 signaling pathway by inhibiting TXNIP, an NLRP3 inflammasome upstream regulator. Furthermore, SAR inhibited the priming signal brought on by NFκB stimulation and the succeeding inflammasome components, cleaved caspase-1, GSDMD, IL-1β, and IL-18. As a result, SAR demonstrated anti-pyroptotic properties in the injured liver. Moreover, SAR exhibited potential antiapoptotic effects, as indicated by decreased Bax levels, decreased tissue expression of cleaved caspase-3, and increased BCL2 levels. Improvements in liver function, oxidative stress markers, liver histology, and the liver weight-to-body weight ratio all supported these findings. In conclusion, SAR demonstrates potential as a preventive treatment for inflammatory liver disorders. To render these preclinical findings into efficient techniques for enhancing hepatic function, more research is required, particularly in the context of diabetes.

This study investigates derivatives including a tetrazole zinc-binding group as inhibitors of the α-, β-, and γ-class carbonic anhydrase (CA) isoforms from pathogenic bacteria such as Vibrio cholerae, Escherichia coli, and Streptococcus mutans. A library of 22 previously synthesized compounds was evaluated for their inhibitory activity against bacterial CAs using a stopped-flow CO₂ hydrase assay. The tetrazole-based inhibitors displayed marked activity toward bacterial α- and β-class CAs, with inhibition constants (K_Is) ranging from 0.43 to 18.7 µM. Among them, 2i and 2p emerged as two of the most potent inhibitors. Selectivity studies showed that only a few compounds exhibited moderate (10- to 20-fold) selectivity for bacterial β-CAs over human CA I, with limited selectivity against human CA II. Molecular modelling studies of the most representative compounds elucidated the key interactions responsible for their potency and selectivity, in agreement with experimental findings. Overall, these results highlight tetrazole derivatives as promising scaffolds for the development of novel antibacterial CA inhibitors.

The estrogen receptor is a central mediator of estrogen-driven gene expression, influencing a wide array of physiological processes. Conventional endocrine therapies, including selective estrogen receptor modulators (SERMs) and degraders (SERDs), often face limitations due to acquired resistance and reduced efficacy in ERα-mutant cancers. Proteolysis-targeting chimeras (PROTACs) serve as a next-generation therapeutic strategy designed to selectively and efficiently degrade estrogen receptor alpha (ERα). The approval of elacestrant further expanded interest in developing novel ERα degraders, shifting the paradigm of drug discovery in this area. This review highlights the mechanism of action of PROTACs, structural and functional domains of ERα, design of PROTACs, and their application in targeting the ERα receptor. Special emphasis is also given on structure activity relationship (SAR) studies and strategies of designing PROTACs reported in the literature, along with in vitro and in vivo studies data. Collectively, these strategies provide valuable insights for designing effective PROTACs to overcome endocrine resistance and advance therapeutic options in ERα-positive breast cancers.

Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products—particularly botanical sources like Yellow Gastrodia elata (YGE)—serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC₅₀ values (0.0145 and 0.0148 mM). Molecular dynamics and network pharmacology analyses further revealed critical interactions between these compounds and key AD-related targets, including ACHE, BCHE, BACE1, and PTGS2. In summary, this work underscores the potential of YGE-sourced compounds, especially parishins A and G, as effective AChE inhibitors. The established integrative computational platform facilitates multi-dimensional bioactivity evaluation and enables hierarchical prioritization of candidate compounds, thereby offering a valuable framework for advancing natural product-derived therapeutics for AD.

This study modified the solvent-exposed region of sunitinib by replacing its diethylaminoethyl tail with linear and heterocyclic amines, guided by lipophilicity, steric, and electronic considerations to enhance the anticancer activity and selectivity. Sunitinib and its 20 derivatives, including 14 new compounds (4a, 4c, 4d, 4g–4i, 5a, 5b, 7a–7e, and 8) and 6 known compounds (4b, 4e–4f, 5c–5d, and 6), were successfully synthesized. The cytotoxic effects of sunitinib and its derivatives were evaluated against three human cancer cell lines (HeLa, SH-SY5Y, and HepG2) and one normal cell line (L929) using the MTT assay. Sunitinib exhibited the strongest cytotoxicity toward SH-SY5Y neuroblastoma cells, with an IC₅₀ of 3.88 µM. Among the derivatives, compound 5b showed the highest potency with an IC₅₀ of 4.28 µM against SH-SY5Y. Compound 6 displayed the highest selectivity index (SI ≥ 5) for HeLa, indicating good selectivity toward cancer over normal cells. Overall, these results suggest that targeted modification of the solvent-exposed region in sunitinib can improve anticancer activity without toxicity against normal cell lines, with compound 5b emerging as a promising lead for further development, particularly against neuroblastoma. The solvent-exposed region is strategic for drug development, allowing modifications that improve affinity, selectivity, solubility, and pharmacokinetics without disrupting ligand-protein interactions.

Cancer prevails a substantial health threat, with breast and colon cancers being the second and third most recurrent worldwide. In recent decades, quinoline/pyrido[2,3-d]pyrimidin-4(3H)-one derivatives have procured attention as propitious anticancer agents. This study acquaint a series of such compounds synthesized and characterized using spectroscopic (1H NMR, 13C NMR, IR, MS) and computational (DFT) methods. Their tubulin polymerization inhibitory and antiproliferative activities were assessed against cancer cell lines MCF-7, MDA-MB-231, and HCT-116, accompanying cytotoxicity screening against normal HEK-293 cells, divulging selective anticancer potential. SAR study accentuated the role of methoxy-substituted phenyl and cycloheptane rings in escalating activity. Peculiarly, compound 4g (IC₅₀ = 3.02 ± 0.63 μM against cell line MCF-7) exhibited profound tubulin inhibition and was additionally substantiated via molecular docking and dynamics simulations, ratifying its drug-like behavior.