Archiv der Pharmazie最新文献

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like cysteine protease (PLpro) represents one of only two essential cysteine proteases involved in the regulation of viral replication. It, therefore, qualifies as a promising therapeutic target for the development of antiviral agents. We identified a previously synthesized protease inhibitor, resulting from an earlier project, as a PLpro inhibitor and crafted a structure–activity relationship around the hit, leading to the more potent inhibitors ZHAWOC6941 (17h) and ZHAWOC25153 (17o) displaying IC₅₀ values of 8 and 7 µM, respectively. The two compounds represent a new class of PLpro inhibitors and, with single-digit micromolar IC₅₀ values, are comparable to inhibitors found in the literature.

Betanin (BET) has been studied for its therapeutic benefits in various diseases, but its low bioavailability and uncertain brain penetration limit its efficacy. Accordingly, this study aimed to explore BET-loaded liposomal nanocarriers (LPN) as a novel treatment for Alzheimer's disease (AD), focusing on the triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX-activating protein of 12 kDa (DAP12) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways implicated in AD. In an AlCl₃-induced AD rat model, 48 male Wistar rats were divided into four groups: control, AlCl₃ (50 mg/kg, intraperitoneal), AlCl₃+BET (100 mg/kg, per os), and AlCl₃+BET LPN (25 mg/kg, intranasally), with treatments administered for 28 days. Morris water maze test and histopathological examination showed that BET LPN-treated rats had improved spatial and learning memory and less hippocampal and cortical degeneration compared with the AlCl₃ and oral BET groups. Mechanistically, BET LPN treatment corrected AD biomarkers, increased miR-132 and ADAM10 expression, and reduced oxidative stress, inflammation, and apoptosis. Additionally, BET LPN treatment suppressed the expression of TREM2, DAP12, ERK1/2, and mitogen-activated protein kinase 1/2 (MEK1/2), showing greater improvement than oral BET. These findings suggest that BET LPN enhances cognitive function and neuroprotection in AD by modulating miR-132 and ADAM10 and inhibiting ERK1/2 and TREM2/DAP12 pathways, providing a more effective treatment compared with traditional oral BET administration.

The seasonal variation in essential oil from four Tabebuia species, T. impetiginosa, T. rosea, T. argentea, and T. guayacan, was explored using gas chromatography–mass spectrometry analysis. A total of 90 components were tentatively identified. Among the four Tabebuia species, the most predominant components in spring were phytol (67.5%), limonene (50.1%), (Z,Z,Z)-7,10,13-hexadecatrienal (67.5%), and 1-octen-3-ol (80.4%), respectively. Chemometric discrimination of the four Tabebuia species was performed employing principal component analysis, which classified the samples into three main clusters while the rest of the samples were scattered in the whole plot. The season of collection impact on essential oils composition and yield was illustrated. 5-Lipooxygenase inhibitory effect of spring season essential oils was assessed, showing that all essential oils exhibited certain inhibition, where T. rosea showed the most potent effect, exhibiting an IC₅₀ value of 1.8 μg/mL, compared to the standard zileuton (0.68 μg/mL). Moreover, an in silico molecular docking study was performed for the predominant metabolites against the 5-LOX active pocket. Among all the docked compounds, eicosane showed the best fitting score, then norphytane, with ∆G of −38.39 and −29.77 kcal/mol, respectively. Thus, Tabebuia species could offer a natural and relatively safe anti-inflammatory candidate that requires further clinical trials to be supported.

Drug-induced hypotension can be harmful and may lead to hospital admissions. The occurrence of hypotension during drug therapy is preventable through increased awareness. This scoping review aimed to provide a comprehensive overview of antihypertensive and nonantihypertensive drugs associated with hypotension in adults. A systematic literature search was conducted using MEDLINE, Embase and Cochrane Library, focusing on studies from January 2013 to May 2023. Search terms were developed to capture key concepts related to hypotension and adverse drug events in adults while excluding terms related to allergic reactions, phytotherapy and studies involving paediatric, pregnant or animal populations. The eligibility criteria included a wide range of study types evaluating hypotension as an adverse drug event across all healthcare settings. Relevant information was extracted from the included studies, while identified drugs associated with hypotension were categorised into drug classes. The review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. In 97 eligible studies, we identified 26 antihypertensive drugs grouped into nine different antihypertensive classes and 158 other drugs grouped into 22 other drug classes. Common antihypertensive classes were angiotensin-converting enzyme inhibitors, beta blockers and diuretics. Frequently reported nonantihypertensive classes were neuroleptics, alpha-1 blockers for benign prostatic hyperplasia, benzodiazepines, opioids and antidepressants. The results highlight the importance of healthcare professionals being aware of nonantihypertensive drugs that can cause hypotension. This review provides a basis for future systematic reviews to explore dose-dependence, drug–drug interactions and confounding factors.

Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology-derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB-inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF-κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF-κB activation pathway. The introduction of heterocyclic substituents in position 2 of the imidazolone core provides compounds with affinity against human NIK. Three candidates, with best affinity profile, were tested in phenotypic experiments of noncanonical NF-κB activation, confirming that the derivative bearing the 4-pyridyl ring can inhibit the processing of NFκB p100 to NFkB2 p52, which is NIK-dependent in cultured kidney tubular cells. Finally, exhaustive docking calculations combined with molecular dynamics studies led us to propose a theoretical binding mode and rationalize affinity measures, in which the aminopyridine motif is a key anchoring point to the hinge region thanks to several hydrogen bonds and the interaction of heterocyclic rings in position 2 with Ser476 and Lys482. Our result will pave the way for the development of potential drug candidates targeting NIK in the context of CKD.

Due to their versatile properties, phenolic compounds are integral to various biologically active molecules, including many pharmaceuticals. However, their application in drug design is often hindered by issues such as poor oral bioavailability, rapid metabolism, and potential toxicity. This review explores the use of phenol bioisosteres–structurally similar compounds that can mimic the biological activity of phenols while potentially offering improved drug-like properties. We provide an extensive analysis of various phenol bioisosteres, including benzimidazolones, benzoxazolones, indoles, quinolinones, and pyridones, highlighting their impact on the pharmacokinetic and pharmacodynamic profiles of drugs. Case studies illustrate the successful application of these bioisosteres in enhancing metabolic stability, receptor selectivity, and overall therapeutic efficacy. Additionally, the review addresses the challenges associated with phenol bioisosterism, such as maintaining potency and avoiding undesirable side effects. By offering a detailed examination of current strategies and potential future directions, this review serves as a valuable resource for medicinal chemists seeking to optimize phenolic scaffolds in drug development. The insights provided herein aim to facilitate the design of more effective and safer therapeutic agents through strategic bioisosteric modifications.

Radioprotectors are synthetic compounds, natural products, or biological agents that are administered before irradiation to protect normal cells against ionizing radiation (IR)-induced injuries. We have designed novel hybrid (E)-kojyl-styryl-sulfones 10a–n by applying the pharmacophore hybridization strategy to combine key structural motifs of the natural antioxidant kojic acid and the emerging radioprotector Ex-RAD (recilisib sodium). These hybrids were successfully synthesized and characterized with (E)-geometry. In vitro radioprotective activity along with the corresponding O-benzylated and O-methoxylated derivatives (9a–n, 14, and 15) was evaluated on human foreskin fibroblast 1 (HFF-1) cells irradiated with a 10-Gy dose of X-rays. In particular, hybrids 10b, 10d, 10f, 10g, and 10n exhibited the highest radioprotection effect at the 10 µM concentration, more effective than the parent compounds. It should be noted that the 3,4,5-trimethoxystyryl analog 10n was the most effective compound. Surprisingly, the O-benzylated 3,4,5-trimethoxystyryl analog (9n) also showed an excellent radioprotective effect. Moreover, the antioxidant evaluation of these selected hybrids on the IR-induced reactive oxygen species (ROS) generation and lipid peroxidation in the HFF-1 cells revealed that they could significantly downregulate IR-induced oxidative stress in the HFF-1 cells, while mechanistically recilisib is not a well-established ROS scavenger. The obtained results suggest that these privileged (E)-kojyl-styryl-sulfones can serve as promising radioprotectors for further studies and development.

Necroptosis is a regulated inflammatory cell death process that is closely associated with autoimmune diseases, acute ischemic injuries, neurodegenerative disorders, and so on. Due to the crucial role of receptor-interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis-related diseases. In this article, we reported a series of pyridazin-4-one derivatives as potent necroptosis inhibitors for both human and mouse cells. The representative compound 13 exhibited favorable RIPK1 selectivity and dose-dependently inhibited RIPK1 phosphorylation. The in vivo pharmacokinetic study indicated that compound 13 was an orally available candidate. Finally, molecular docking and molecular dynamics simulations were performed to elucidate the binding pattern of compound 13 with RIPK1. Collectively, compound 13 represents a promising lead compound for the future development of RIPK1-targeted necroptosis inhibitors.

Methotrexate (MTX) is commonly employed in cancer treatment, but its clinical use is restricted due to the MTX-associated renal injury. This study investigates the combined potential of Rhus coriaria (sumac) and bone marrow mesenchymal stem cells (BMMSCs) against MTX-induced nephrotoxicity in rats. The high-resolution-liquid chromatography-mass spectrometry (HR-LC-MS) of sumac extract tentatively identified 22 phytochemicals, mostly flavonoids, anthocyanins, and steroids. Preparation of sumac liposomes attained a suitable particle size of 3041.33 ± 339.42 nm, a polydispersity index of 0.208 ± 0.086, and an encapsulation efficiency of 84.92 ± 3.47%. Rat BMMSCs were injected into the tail vein of the experimental rats (0.5 × 10⁶ cells, intravenous [iv]) of seven treated groups. The experimental design relies on either pre- or posttreatment of rats with intraperitoneal (IP) sumac liposomes (SL) (200 mg/kg, daily with a dose of MTX (300 µg/kg/14 days). The histopathological examination and serum analysis of creatinine and urea revealed good results, besides regulating levels of oxidative stress and inflammatory markers. Additionally, a significant decrease in the gene expression levels of B-Cell Lymphoma 2 (Bcl-2) and caspases-3 and −9, a remarkable increase in the Bcl-2 Associated X-Protein (Bax), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme-oxygenase 1 expression, and a downregulation of Kelch-like ECH-associated protein 1 (Keap1). Collectively, the coadministration of SL with BMMSCs might be a potent therapeutic strategy for attenuation of MTX-induced renal damage. The network pharmacology analysis identified the involved key hub genes as KEAP1, Nrf2, HMOX1, mitogen-activated protein kinase (MAPK1), nuclear factor-kappa B (NF-KB), interleukin-1 beta (IL-1B), and caspase-3. The docking results revealed strong binding affinities of 7-O-methyl-cyanidin-3-O-(2″-galloyl)-galactoside with Keap1 and amentoflavone with MAPK. These insights pave the way for future experimental validation and therapeutic development of sumac-based phytoconstituents against MTX-induced nephrotoxicity.