European Journal of Medicinal Chemistry Reports最新文献

Rheumatoid arthritis, classified as an immune system disorder, stands as a prevalent condition that presents considerable challenges to healthcare systems worldwide. This study was delving into the realm of traditional medicine to explore the use of medicinal plants for the treatment of rheumatoid arthritis and immune system disorders in the Casablanca-Settat region of Morocco. With a focus on ethnopharmacological insights, a comprehensive survey was conducted involving 372 participants, including herbalists and patients, to document the local knowledge and practices associated with these conditions. The findings revealed a noteworthy reliance on traditional medicinal knowledge, with a prominent role played by females across different age groups. A diverse spectrum of 88 plant species hailing from 45 distinct families was identified, where in the Myrtaceae, Oleaceae, and Zingibneraceae families garnered prominence as the most endorsed choices. Noteworthy among these, Zingiber officinale and Curcuma longa emerged as highly favored species, boasting robust anti-inflammatory and immunomodulatory attributes. The study also offers insight regarding preferences concerning administration methods, highlighting the salience of oral consumption and infusion as the predominant modes of preparation. Nevertheless, the observed variability in dosage utilization underscores the traditional therapeutic paradigmsintricacies. Geographic disparities were discernible as well, with certain species displaying a region-specific usage pattern, further enriching the understanding of local herbal practices. Moreover, the study identified endemic species such as Olea europaea, Teucrium polium, Argania spinosa, and Withania adpressa contributing to the safeguarding of the region's indigenous botanical heritage. In conclusion, this study contributes to a deeper understanding of the traditional management of RA and immune system disorders in the Casablanca-Settat region. The documented plant species, practices, and preferences offer valuable insights into potential sources of anti-inflammatory and immunomodulatory agents.

Cancer is an expansionist disease, it invades through tissues, sets up colonies in hostile landscapes, seeking “sanctuary” in one organ and then immigrating to another. Ovarian and colorectal cancer has high mortality rates in India. Colorectal cancer typically begins in the gut lining and can spread through the colon wall and beneath the muscular layers, and is a significant source of morbidity. Ovarian cancer has the highest recurrence rate of all gynaecologic cancers and has high mortality because of late diagnosis brought on by vague symptoms. In this review article, we have discussed that apart from the conventional ways of treatment, how nanoparticles has the potential to improve the detection, diagnosis, and treatment of these cancers. Liposomal nanoparticles are lipid-based vesicles that can encapsulate drugs and deliver them to specific targets in the body, potentially improving the effectiveness and reducing the side effects of the treatment. This article also provides an insight on the fact that while liposomal nanoparticles show promising effect, there are challenges to be addressed, including optimizing drug release rates, and ensuring effective targeting.

Mitotic kinesin-like protein 2 (MKLP2/KIF20A) is a key mitotic regulator frequently overexpressed in human malignancies and its abundance is positively correlated with poor outcomes of the disease. Despite extensive research on MKLP2 as a potential target for oncology, the development of small-molecule inhibitors specific to MKLP2 remains limited. We have previously identified a benzoazipinone compound, HJ81 as a potent disruptor of Aurora kinase B (AURKB) localization during late mitosis. This study reveals that such disruption results from a failure of AURKB relocation at the onset of anaphase and this phenomenon can be specifically attributed to the disablement of MKLP2, a recognized facilitator of the relocation process. Further optimization of HJ81 leads to identifying compounds such as 12a as promising lead inhibitors of MKLP2-mediated processes, with improved pharmacokinetic properties. 12a inhibits the microtubule-stimulated ATPase activity of the recombinant MKLP2 in vitro. Significant suppression of tumor growth was observed in mice bearing the Calu-6 lung cancer cell line when treated with 12a at a well-tolerated dose. Overall, our findings suggest that benzoazipinone derivatives represent a novel chemical scaffold with the potential to be developed to mimic MKLP2 inhibition for cancer treatment.

Portulaca oleracea is rich in several minerals, vitamins, and antioxidant components, which has made it widely used in the management of hepato-renal disorders. In this study, we aimed to establish the safety or otherwise effect of Portulaca oleracea on renal function in albino Wistar rats concerning its numerous uses in traditional medicine as a vegetable for humans and as animal feed. The rats were grouped into experimental and control groups of ten (10) rats each. The experimental group was fed with 200 mg/kg of portulaca oleracea extract incorporated into the diet, while the control group was fed with normal feed for 4 weeks. Blood samples were collected for analysis. The data obtained was analyzed using a student t-test. The result of the test showed that creatinine from the experimental group (0.28 ± 0.03 mg/dL, p = 0.002) showed a significant decrease when compared with the control group (0.37 ± 0.02 mg/dL) at p<0.05. Urea from the experimental group (28.57 ± 2.77 mg/dL, p = 0.002) showed a significant decrease as compared to the control group (37.175 ± 2.27 mg/dL). Sodium (174.66 ± 5.38 mEq/L, p = 0.007), potassium (13.07 ± 0.48 mEq/L, p = 0.016) and calcium (9.94 ± 1.05 mEq/L, p = 0.043) of portulaca group showed significant increase when compared with their respective control values (143.19 ± 4.70; 9.22 ± 3.10; 8.52 ± 0.83mEq/L) at p<0.05. It could therefore be concluded that Portulaca oleracea extract at a dose level of 200 mg/kg has a beneficial effect on renal function by enhancing creatinine and Urea clearance and improving serum sodium, potassium and calcium concentration.

Breast cancer (BC) is the leading cause of death among women worldwide. According to the Breast Cancer Research Foundation (BCRF), 25% of all cases of BC are positive for human epidermal growth factor receptor 2 (HER2), which is the most aggressive phenotype among the five BC subtypes. Previous studies have reported that the epidermal growth factor receptor (EGFR) is also overexpressed in HER2-positive BC, which elevates disease severity. Based on these findings, the present study aimed to identify dual inhibitors of EGFR and HER2 by employing chemometric modelling techniques. A dataset of chemical molecules with affinity for both EGFR and HER2 was prepared by literature review. The dataset was split into training and test sets based on the inhibitory concentration (IC₅₀) for EGFR and HER2. The training set was used to generate two pharmacophore models, one each for EGFR (n = 30, R² value = 0.82 with RMSD = 1.4, Δ cost = 151.84, and configuration cost = 20.3) and HER2 (n = 30, R² value = 0.84 with RMSD = 1.0, Δ cost = 68.47, and configuration cost = 22.2). The developed models were validated using the test set (n = 214 and 201, andR²_pred = 0.73 and 0.70, for EGFR and HER2, respectively), decoy set (decoys = 104, actives = 18), and an external dataset (n = 20). The robustness of the models was validated using Fischer's randomization method (at 95% confidence) and applicability domain analysis. The validated models for EGFR and HER2 were used to screen the Asinex library (n = 575,302) for identifying consensus hits against both targets. Molecules with predicted IC₅₀ < 20 nM were subsequently screened, and their toxicity profiles were evaluated using ProTox II. The interactions, ligand efficiency, and binding affinities of the selected compounds were assessed from the docking scores and molecular mechanics with generalized Born and surface area solvation (MMGBSA) energy. Hit selection against EGFR and HER2 was finally achieved by molecular dynamics simulations using the OPLS4 force field in Desmond. The identified hit can serve as a reference for developing dual inhibitors of EGFR and HER2 in future.

Viral infections account for a large proportion of the total number of fatal diseases and require close attention from the international public health community. The COVID-19 pandemic has highlighted problems in medicine and healthcare related to the search for effective substances for the prevention, diagnosis and treatment of viral infections. According to many scientific studies, cerium species are very promising biomedical materials for combatting viral infections and have shown encouraging results in killing viruses on non-living objects, reducing viral load both in vitro and in vivo, relieving symptoms and reducing the consequences of viral diseases. This review critically examines the current level of knowledge on cerium species and their practical applications, with a focus on CeO₂ nanoparticles (CeNPs). This review also seeks to assess the prospects for their development and use in antiviral theranostics.

Among cancer-related disorders, lung carcinoma is one of the leading causes of mortality. Anaplastic lymphoma kinase (ALK) belongs to tyrosine kinase receptor family and exhibits similar characteristics to insulin type receptors. The treatment of advanced non-small cell lung cancer (NSCLC) associates with ALK gene rearrangement has significantly improved since the approval of Crizotinib in 2011 as the first generation ALK inhibitor. In continuation, the second-generation drugs like ceritinib, alectinib, and brigatinib were developed to address and counteract resistance that was associated with the first-generation agents. However, resistance can develop over time, necessitating ongoing research to enhance their effectiveness. Therefore, the third-generation drug lorlatinib, which has demonstrated broad-spectrum potency against the majority of known resistance mutations and better lipophilicity, has been developed. According to current reports, the USFDA has approved five ALK-TKIs crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib for ALK-associated lung cancer. Currently, several clinical trials are underway in search of better ALK inhibitors. Trials such as TPX-0131 and NVL-655 are considered fourth-generation ALK inhibitors for the treatment of patients with advanced ALK-positive or metastatic NSCLC. This review aims to provide specifics information on research works involving various ALK tyrosine kinase inhibitors, clinical studies, and the development of ALK TKIs. Additionally, we suggest potential future strategies involving sequential therapy and combination techniques for managing non-small cell carcinoma.

Earlier studies had shown the potential of modified pentacyclic triterpenes as possible inhibitors of carbonic anhydrase II (CA II). In an extension of our earlier studies, betulin, betulinic acid and, for comparison purposes, glycyrrhetinic acid, ursolic acid and oleanolic acid were therefore converted into the respective acetates and linked to either taurinamide or de-acetylated acetazolamide via a variable linker. In particular, the derivatives 8 and 18 derived from betulinic acid or betulin and provided with a long spacer were found to be strong competitive inhibitors of CA II, thereby holding K_i = 1.27 and 0.20 μM, respectively.

The successful nickel catalyzed synthesis of N-(aryl) substituted p-toluene sulphonamides is reported. The intermediate 4-methylbenzenesulphonamide was obtained by the reaction of p-toluenesulphonyl chloride and ammonium hydroxide. Substituted p-toluene sulphonamides were obtained by coupling 4-methylbenzenesulphonamide with readily available aryl halides via Buchwald-Hartwig cross-coupling reaction. The structures of the compounds were confirmed using Fourier Transform Infrared (FT-IR), proton NMR, carbon-13 NMR and mass spectroscopy. The new compounds were screened for antibacterial and antifungal activities against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Aspergillus niger using agar diffusion technique. Some of the compounds showed improved antimicrobial activity when compared with ciprofloxacin and ketoconazole. The sulphonamides were further screened for antioxidant activity using 1,1-diphenyl-2-picrylhydrazide (DPPH), ferric reducing antioxidant potency (FRAP) and ferrous sulphate induced lipid peroxidation. The compounds showed improved antioxidant activity on comparison with ascorbic acid. Specifically, compound 20 was revealed by this study to be a lead antibacterial and antifungal agent whereas compound 17 showed a lead as antioxidant agent. The drug-likeness study indicated that none of the compounds violated Lipinski, Ghose, and Verber rules for drug-able molecules.

The treatment of psychiatric disorders is still an unresolved problem in our society and schizophrenia, the 12th cause of disability in the world, is an important and serious mental disorder. This short review presents a comprehensive overview of the gold standard clozapine developed approximately seven decades ago, which can be considered a milestone in the development of new antipsychotics. It is the first atypical antipsychotic to enter clinical use and is recognized for the treatment of psychiatric illnesses such as schizophrenia and bipolar disorder, as its efficacy is superior to other antipsychotic agents like chlorpromazine. Clozapine is a 5-HT2A and D2 receptor antagonist, as well as a 5-HT1A receptor agonist.