Archiv der Pharmazie最新文献

Steroid dimers of natural and synthetic origin possess an unusual and complex molecular architecture that may lead to the realization of peculiar effects in biological systems, in particular in different cancer cell lines. In the present work, diastereoselective ring-opening of mono- and polyoxiranes, containing a cyclooctane core, by azide-anion was performed to yield a series of azidoalcohols with different types of symmetry. The products were involved in copper-catalyzed azyde-alkyne cycloaddition (CuAAC) reaction with ethinylestradiol and ethinyltestosterone, and the resulting steroids and steroid dimers with triazole linkers were screened for their antiproliferative activity via (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide) assay. All the compounds revealed cytotoxicity toward several cancer cell lines. The effect of the most potent compound, containing two estradiol moieties, on the microtubules (MT) dynamics was investigated by immunofluorescent microscopy. The disruption of the majority of interphase cell cytoplasmic MT and mitotic event disturbances in the presence of the studied compound were observed. The latter effect caused the appearance of numerous multinucleated cells.

Glioblastoma multiforme is a very combative and threatening type of cancer. The standard course of treatment involves excising the tumor surgically, then administering chemotherapy and radiation therapy. Because of the presence of the blood–brain barrier and the unique characteristics of the tumor microenvironment, chemotherapy is extremely difficult and has a high incidence of relapse. With their capacity to precisely target and transport therapeutic medications to the tumor while overcoming the challenges provided by invasive and infiltrative gliomas, nanocarriers offer a potentially beneficial treatment option for gliomas. Drug repositioning or, in other words, finding novel therapeutic uses for medications that have received approval for previous uses has also recently emerged to provide alternative treatments for many diseases, with glioblastoma being among them. In this article, our goal is to shed light on the pathogenesis of glioma and summarize the proposed treatment approaches in the last decade, highlighting how combining repositioned drugs and nanocarriers technology can reduce drug resistance and improve therapeutic efficacy in primary glioma.

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.

Phenothiazine (PTZ) derivatives have been acknowledged as versatile compounds with significant implications across various areas of medicine, particularly, in cancer research. The cytotoxic effects of synthesized compounds on both normal and cancerous cells, along with their oxidant–antioxidant properties, are pivotal factors in cancer treatment strategies. In the current study, eight new PTZ derivatives were synthesized and the compounds' cytotoxic activities were assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay while the oxidant–antioxidant properties were evaluated by oxidative stress index (OSI) calculation in SH-SY5Y (a human neuroblastoma cell line), HT-29 (a human colorectal adenocarcinoma cell line), and PCS-201-012 (a human primary dermal fibroblast cell line) cells. Consequently, the half-maximal inhibitory concentration (IC₅₀) values of compound 3a were determined to be 218.72, 202.85, and 227.86 μM while the IC₅₀ values of compound 3b were defined to be 227.42, 199.27, and 250.11 μM in PCS-201-012, HT-29, and SH-SY5Y cells, respectively. Additionally, it was determined that the synthesized compounds demonstrated the lowest OSI in PCS-201-012 cells as compared to the other cell lines.

A new series of muscarinic acetylcholine receptor (mAChR) ligands obtained by inserting different substituents in position 2 of the potent 6,6-diphenyl-1,4-dioxane antagonists 4 and 5 was designed and synthesized to investigate the influence of steric bulk on the mAChR affinity. Specifically, the insertion of a 2-methyl group, affording compounds 6 and 9, resulted as the most favorable modification in terms of affinity for all muscarinic subtypes. As supported by computational studies performed on the hM₁ receptor, this substituent may contribute to stabilize the ligand within the binding site by favoring the formation of stable interactions between the cationic head of the ligand and the residue D105. The increase of steric bulk, obtained by replacing the methyl group with an ethyl (7 and 10) and especially a phenyl substituent (8 and 11), caused a marked decrease of mAChR affinity, demonstrating the crucial role played by the steric bulk of the 2-substituent in the mAChR interaction. The most intriguing result was obtained with the tertiary amine 9, which, surprisingly, showed two different pK_i values for all mAChRs, with preferential subpicomolar affinities for the M₁, M₃, and M₄ subtypes. Interestingly, biphasic curves were also observed with both the eutomer (S)-(–)-9 and the distomer (R)-( + )-9.

The inhibitory potential of 17 flavonoids on lactate dehydrogenase A (LDHA), a key enzyme in the downstream process of aerobic glycolysis in cancer cells, is investigated. Fisetin exhibited excellent inhibitory activity (IC₅₀ = 0.066 µM). Quercetin 3-β-D-glucoside, quercetin 3-galactoside, luteolin, neoeriocitrin, and luteolin 7-O-β-D-glucoside showed good inhibitory activity (IC₅₀ = 1.397–15.730 µM). Biochanin A, baicalein, quercetin, scutellarein-7-glucuronide, diosmetin, baicalein 7-O-β-D-glucuronide, and apigenin 7-apioglucoside demonstrated moderate inhibitory activity (IC₅₀ = 33.007–86.643 µM). Eriodictyol, quercetin 7-O-β-D-glucoside, apigenin 7-O-β-D-glucoside, and epicatechin were inactive. The Lineweaver–Burk plot showed that fisetin competitively inhibits NADH binding (K_i = 0.024 µM). K_i values for other compounds were calculated using the Cheng–Prusoff equation (K_i = 0.2799–2.1661 µM). The study revealed that the inhibitory effect of flavonoids varies with the number and position of OH groups and bound sugars. Molecular docking analyses indicated that flavonoids exhibited strong interactions with the NADH binding site of LDHA through hydrophobic interactions and hydrogen bonds. Molecular dynamic simulations tested the stability of the fisetin-LDHA complex over 100 ns and showed fisetin's high binding affinity to LDHA, maintaining strong hydrogen bonds. The binding energy of fisetin with LDHA was −33.928 kcal/mol, indicating its effectiveness as an LDHA inhibitor. Consequently, flavonoids identified as strong inhibitors could be potential cancer treatment sources through LDHA inhibition.

Chronic wounds significantly impact the patients' quality of life, creating an urgent interdisciplinary clinical challenge. The development of novel agents capable of accelerating the healing process is essential. Caffeic acid phenethyl ester (CAPE) has demonstrated positive effects on skin regeneration. However, its susceptibility to degradation limits its pharmaceutical application. Chemical modification of the structure improves the pharmacokinetics of this bioactive phenol. Hence, two novel series of CAPE hybrids were designed, synthesized, and investigated as potential skin regenerative agents. To enhance the stability and therapeutic efficacy, a caffeic acid frame was combined with quinolines or isoquinolines by an ester (1a–f) or an amide linkage (2a–f). The effects on cell viability of human gingival fibroblasts (HGFs) and HaCaT cells were evaluated at different concentrations; they are not cytotoxic, and some proved to stimulate cell proliferation. The most promising compounds underwent a wound-healing assay in HGFs and HaCaT at the lowest concentrations. Antimicrobial antioxidant properties were also explored. The chemical and thermal stabilities of the best compounds were assessed. In silico predictions were employed to anticipate skin penetration capabilities. Our findings highlight the therapeutic potential of caffeic acid phenethyl ester (CAPE) derivatives 1a and 1d as skin regenerative agents, being able to stimulate cell proliferation, control bacterial growth, regulate ROS levels, and being thermally and chemically stable. An interesting structure–activity relationship was discussed to suggest a promising multitargeted approach for enhanced wound healing.

Mohamed H. M. AbdEl-Azim, Maged A. Aziz, Samar M. Mouneir, Ahmed F. EL-Farargy, Wesam S. Shehab. Ecofriendly synthesis of pyrano[2,3-d]pyrimidine derivatives and related heterocycles with anti-inflammatory activities. ArchPharm, 353, 1. https://doi.org/10.1002/ardp.202000084

Autor name “Maged Abdelaziz” corrected to “Maged A. Aziz”.

A new series of benzimidazole-oxindole hybrids 8a–x was discovered as dual cyclin-dependent kinase (CDK2) and glycogen synthase kinase-3-beta (GSK-3β) inhibitors with potent anticancer activity. The synthesized hits displayed potent anticancer activity against national cancer institute cancer cell lines in single-dose and five-dose assays. Moreover, the derivatives 8k, 8l, 8n, 8o, and 8p demonstrated potent cytotoxic activity against PANC-1 cells with IC₅₀ = 1.88–2.79 µM. In addition, the hybrids 8l, 8n, 8o, and 8p displayed potent antiproliferative activity on the MG-63 cell line (IC₅₀ = 0.99–1.90 µM). Concurrently, the benzimidazole-oxindole hybrid 8v exhibited potent dual CDK2/GSK-3β inhibitory activity with IC₅₀ values of 0.04 and 0.021 µM, respectively. In addition, 8v displayed more than 10-fold higher selectivity toward CDK2 and GSK-3 β over CDK1, CDK5, GSK-3α, vascular endothelial growth factor receptor-2, and B-rapidly accelerated fibrosarcoma. Screening of the effect of 8n and 8v on the cell cycle and apoptosis of PANC-1 and MG-63 cells displayed their ability to arrest their cell cycle at the G2-M phase and to potentiate the apoptosis of both cell lines. In silico docking of the benzimidazole-oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK-3β revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a–x exhibit satisfactory drug-likeness properties for drug development.

Rifaximin, a broad-spectrum antibiotic, boasts a unique chemical composition and pharmacokinetic profile, rendering it highly effective in treating irritable bowel syndrome (IBS). Its minimal systemic absorption confines its impact to the gastrointestinal (GI) tract, where it yields significant therapeutic benefits. This review examines rifaximin's physico-chemical attributes and its role in managing IBS symptoms. Its molecular structure facilitates intestinal lumen retention postoral administration, minimizing systemic exposure and adverse effects. This targeted action is crucial in addressing the gut microbiota's role in IBS pathophysiology. By modifying microbial populations and their metabolite production, rifaximin mitigates symptoms like bloating, irregular bowel habits, and abdominal pain associated with IBS. It achieves this by reducing pathogenic bacteria and altering bacterial metabolism, enhancing mucosal and immune function. Clinical trials affirm rifaximin's superiority over placebo and conventional therapies in alleviating overall IBS symptoms and addressing small intestine bacterial overgrowth (SIBO). Despite its promising efficacy and sustained symptom relief, further research is essential to optimize long-term effectiveness and dosing regimens. Rifaximin stands as a vital treatment option for IBS due to its distinctive properties and clinical utility; yet, ongoing investigation is imperative for maximizing its therapeutic benefits.