Archiv der Pharmazie最新文献

Pregnenolone-carbamate derivatives were synthesized and evaluated as potential multifunctional agents with cholinesterase inhibitory and neuroprotective properties. Among them, P3, P5, and P9 exhibited the most promising profiles and were subjected to integrated spectroscopic, biochemical, and computational analyses. Inhibition assays revealed selective acetylcholinesterase (AChE) inhibition by P3 (IC₅₀ = 0.11 μM), butyrylcholinesterase inhibition (BuChE) selectivity for P5 (IC₅₀ = 0.47 μM), and dual inhibition by P9. Fluorescence and UV–vis studies indicated minor groove binding to DNA with log K_app values around 5.85, while static quenching with human serum albumin (HSA) was observed, with log K_A values up to 2.25. Docking studies supported these findings, showing favorable binding energies for DNA (–8.6 kcal/mol) and HSA (–9.7 kcal/mol), and predicted localization within the DNA minor groove and Sudlow sites on HSA. Cytotoxicity assays on HT22 cells indicated high viability (> 75% at 40 µM), suggesting a favorable safety margin. These results offer a molecular-level understanding of the pharmacodynamic and pharmacokinetic properties of these compounds and support their potential for further in vivo evaluation.

The antineoplastic properties of the Cu(II) coordination compound Casiopeina III-ia (Cas III-ia) are revealed using an in vivo glioma model, and its biopharmaceutical properties are predicted through an in silico analysis. C6 cells of the murine glioma allograft model were implanted in rats to form glioma tumors and treated with Cas III-ia at doses of 0.75 and 1.5 mg/kg/day for 21 days. The mean tumor volume of treated rats was reduced by 73% and 88% compared with the control, respectively. Moreover, the mitotic and proliferation indexes decreased with a simultaneous increase in the apoptotic index. We observed the generation of reactive oxygen species, lipoperoxidation, increased p21WAF/CIP, Bax, cleaved caspase 3, and decreased Cyclin D and Bcl-2. The pharmacokinetic study reveals a half-life of 12.4 h, depuration of 5.3 mL/h, and a volume of distribution of Cas III-ia of 20.3 L. In silico analysis revealed that Cas III-ia possesses potential oral bioavailability, high gastrointestinal absorption, the capacity to penetrate the blood–brain barrier, and is a potential target of glycoproteins, but not a substrate of CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. Our findings strongly suggest that Cas III-ia holds excellent promise as a potential compound for treating human malignant glioma.

Multidrug-resistant (MDR) bacterial infections are on the rise worldwide, and there are fewer clinically available medications to treat them. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most compelling and harmful bacteria. MRSA has surfaced, spread widely, and gained recognition as a leading source of bacterial infections in both community and clinical settings. The most dangerous feature of MRSA is its quick evolution of resistance to all known antibiotics, including vancomycin. Finding novel, powerful, and less hazardous antibiotic moieties is essential to combating MRSA isolates. In medicinal chemistry, the electron-withdrawing groups—primarily the –Cl, NO₂, F, and Br groups—can play an important role. A curative or diagnostic small molecule aspirant's pharmacokinetic and physicochemical characteristics, such as increased membrane permeability for MRSA and better metabolic stability, can be improved by the selective setup of EWGs. In this study, we reviewed the benefits of using EWGs to boost antibacterial effectiveness against different types of bacterial pathogens and talked about how it might be used in antibacterial drug discovery.

Genipin is the primary active pharmacological component of several commonly used traditional Chinese medicines, and it has a variety of applications. In addition to medical uses, it has applications in food and biomaterials. However, because genipin causes dose-dependent hepatotoxicity, it is critical to identify sensitive indicators of genipin-induced dose-dependent hepatotoxicity and explain its mechanism to prevent and treat hepatotoxicity caused by genipin and similar traditional Chinese medicines. This article uses targeted metabolomics, network pharmacology, and molecular docking to screen highly relevant early diagnostic markers of genipin-induced dose-dependent liver injury and then analyzes its toxicological targets to elucidate the mechanism of genipin-induced dose-dependent liver injury. The findings demonstrated that genipin's impact on the associated liver injury targets (GSR, AKR1B1, PTGS1, MAOB, CA2, HSP90AA1, CDK1, LGALS3, HTR2C, LCK, and CASP1) was primarily linked to its disturbance of the metabolic homeostasis of the endogenous metabolites 2-phenylpropionate, 4-hydroxybenzoic acid, propionylcarnitine, and N-acetylaspartic acid. This study serves as a foundation for the early detection and prevention of liver damage brought on by genipin and associated traditional Chinese medicines. It also serves as a guide for further in-depth research into the mechanism underlying genipin-induced liver injury.

Irritable bowel disease or syndrome (IBD/IBS) is a prevalent gastrointestinal tract problem affecting approximately 4% of the total population of the world. Choosing effective pharmacological treatments for IBS is still challenging due to the existence of a heterogeneous type of patient population, diverse expectations, limited availability of effective drugs, and incompletely understood pathophysiology of the disease. Recent advancements in pharmacological research have increasingly focused on neurotransmitter dysfunctions, particularly targeting serotonin and GABA pathways. Therapeutic approaches include the use of 5-HT3 receptor antagonists and 5-HT4 receptor agonists to regulate gastrointestinal motility and sensitivity. Meanwhile, GABA-analogous medications remain underutilized despite their potential to alleviate visceral pain. This study briefly overviews IBS, highlighting its symptoms, potential causes, and chronic nature. Despite its significant societal burden, IBS often lacks attention, necessitating further research to understand its actual costs. The significance of identifying novel therapeutic agents and drug targets in IBS is underscored, offering improved treatment efficacy, reduced side effects, and the potential for personalized medicine. This article aims to explore neuro-immune interactions, evaluate new treatments, and enhance the understanding of IBS to improve treatment outcomes. It emphasizes the importance of identifying innovative therapeutic approaches and drug targets.

Turmeric is a common spice obtained from the rhizomes of the Curcuma longa plant. It belongs to the Zingiberaceae (ginger family). The rhizome is a horizontally growing stem that sends roots and shoots from below ground. Turmeric has many uses, including spice, food preservation, flavor enhancement, and coloring. Also, it is used in conventional medicine as a home treatment for many diseases. Turmeric obtains its yellow color from curcuminoids, polyphenolic pigments that dissolve in fat. The primary curcuminoid form in turmeric is curcumin or diferuloylmethane (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione). It is the most active element and is responsible for its biological characteristics. Curcumin exhibits significant benefits in many human disease treatments. Generally, curcumin is beneficial to human health due to its therapeutic characteristics. These involve antioxidant, anti-inflammatory, anticancer, antiangiogenic, hepatoprotective, neuroprotective, antidiabetic, immunomodulatory, antimicrobial, wound healing, and cardiovascular diseases. Although comprehensive studies have been conducted on curcumin's ability to treat many human diseases, major challenges remain, especially regarding its therapeutic efficacy and bioavailability. This review presents an overview of curcumin's therapeutic applications, its benefits for human health, and the challenges to its broad use. It also highlighted existing solutions and approaches to enhance curcumin's therapeutic potential.

Staphylococcus aureus-associated infections pose a significant clinical challenge due to biofilm formation, which contributes to antibiotic resistance and persistent infections. The prevalence of methicillin-resistant S. aureus (MRSA) further exacerbates this issue, underscoring the urgent need for effective therapeutic strategies. In this study, we report a potent and selective second-generation MRSA biofilm inhibitor (4ad), which showed a minimum biofilm inhibition concentration (MBIC₅₀) of 0.78 µg/mL and demonstrated ≥ 128-fold selectivity for biofilm inhibition over planktonic growth. Through structural optimisation and fragmentation, we further identified a truncated analogue (5a) that effectively eradicated a preformed MRSA biofilm, with a minimum biofilm eradication concentration (MBEC₅₀) of 0.78 µg/mL—outperforming both the first-generation hit (4e) and the clinically used antibiotics oxacillin and vancomycin. Notably, both 4ad and 5a exhibited no significant impact on planktonic bacterial viability or Vero cell cytotoxicity. Given the broad-spectrum antibiofilm activity of 4e against S. aureus, we investigated its combinatorial effects with antibiotics. 4e demonstrated additive effects in combination with vancomycin, erythromycin, and amoxicillin. Importantly, both structure–activity relationship (SAR) and quantitative structure–activity relationship (QSAR) analyses identified key structural features associated with antibiofilm activity. Collectively, these findings support further development of pyrazolyl indolenine derivatives and mechanistic studies aimed at combating antibiotic-resistant S. aureus biofilm.

Ripretinib (QINLOCK) is a broad-spectrum, orally-administered, switch-controlled kinase inhibitor that got FDA approval in May 2020 for the treatment of advanced gastrointestinal stromal tumors (GIST) in adult patients who have formerly had treatment with three or more kinase inhibitors, comprising imatinib. This study sought to develop a precise, rapid, dependable, and sustainable UPLC-MS/MS approach for measuring ripretinib (RPB) in the human liver microsomes (HLMs) matrix, utilized for assessing the metabolic stability of RPB. The validation processes for the UPLC-MS/MS system adhered to US-FDA rules for bioanalytical technique validation. The validated method utilized HLMs matrix throughout a level range of 1–4000 ng/mL with a duration of 1 min. The precision (%RSD) and accuracy (%E) rates for intraday and interday measurements varied from –0.6% to 9.3% and –2.5% to 15.3%, respectively. The StarDrop software employed P450 and DEREK modules to evaluate metabolic lability and to characterize RPB structural warnings, respectively. The in-vitro t_1/2 was calculated to be 47.4 min, and the intrinsic clearance (Cl_int) of RPB was computed to be 17.1 mL/min/kg. In-silico assessments indicate that slight structural changes to the methyl amino group (97%) and the phenylurea moiety (3%) in drug design could increase the metabolic stability of RPB. The evaluation of in-silico RPB ADME characteristics and metabolic stability is fundamental for progressing innovative drug research focused on augmenting metabolic stability.

A serious, rapidly growing global health issue is diabetes mellitus (Type 2) caused by insulin deficiency or insulin resistance. This is a chronic condition that demands ongoing care and management. Although a variety of anti-hyperglycaemic medications are available, the need for safer, more effective, and affordable antidiabetic treatments remains crucial due to the undesirable side effects associated with existing options. This review primarily highlights the innovative sodium-glucose co-transporter 2 (SGLT-2) inhibitors and explores their various characteristics. Gliflozins represent an important class of medications used to manage type II diabetes by targeting the SGLT2. By inhibiting SGLT2, they effectively reduce blood glucose levels by preventing the kidneys from reabsorbing glucose. This review offers a comprehensive overview of gliflozins approved by leading regulatory authorities such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA). It explores the design and development of sodium-glucose co-transporter (SGLT) inhibitors, their mechanisms of action, structure–activity relationships, and additional therapeutic applications.