Future medicinal chemistry最新文献

Background: Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer that remains incurable because it is often detected at an advanced stage, making treatment difficult.

Martials and methods: The reaction of free metformin (5) with isothiocyanate derivatives (6-9) and the or with 4-toluenesulfonyl isocyanate (10) afforded the targeted metformin analogues (11-15). The in vitro anticancer impact of these compounds was assessed using cell lines of BJ1, PACA2, and HePG2.

Results: Compound 13 had significant cytotoxic effects against PACA2 and HePG2 with mortality 88.30% and 71.20%, respectively. In a chronic study, the body weights of male rats receiving 13 at a dose of 50 mg/kg for 12 consecutive weeks showed an insignificant difference in the percentage change in body weight. Histopathological examination of the pancreas and liver with 13 exhibited normal histological structure of exocrine and endocrine parts. Additionally, normal cardiac myocytes were observed in the heart of rats treated with 13.

Conclusions: It can be inferred that the daily administration of 50 mg/kg of compound 13 over a duration of 12 weeks did not elicit any substantial alterations in body weight, biochemical, hematological, or histopathological parameters, while concurrently exhibiting pronounced anticancer efficacy against pancreatic ductal adenocarcinoma (PDAC).

Carbocycles have been widely employed in the development of pharmaceutically active scaffolds. Cyclopropane has attracted significant attention from researchers due to its unique chemical properties among carbocycles. Subsequently, this review will focus on cyclopropane-containing pharmaceutical drug products that have been approved by the FDA (Food and Drug Administration) and are used to treat a wide variety of medical conditions. In addition to the synthesis of the cyclopropyl moiety through various chemical reactions, such as the Corey-Chaykovsky reaction and the Simmons-Smith reaction. Several cyclopropane-containing pharmaceutical drugs have been reported to exert significant anti-coagulant effects. Additionally, they also exhibit inhibitory activity against MET, a receptor tyrosine kinase, as well as vascular endothelial growth factor receptor 2 (VEGFR-2). Moreover, they showed cytotoxicity by inhibiting epidermal growth factor receptor (EGFR^L858R/T790M). In addition to antidiabetic, anti-Alzheimer, antimalarial, antimicrobial, anti-convulsant and anti-depressant activities. Herein, we present the pharmaceutical applications of cyclopropane-containing derivatives, shedding light on the structure-activity relationship (SAR), along with some commonly reported methods for their synthesis.

Ferroptosis is a form of Regulated Cell Death (RCD) found in recent years. Its typical characteristics are the abnormal accumulation of intracellular iron ions and the accumulation of lipid peroxidation products. Since its first systematic elucidation in 2012, a large number of studies have shown that ferroptosis is involved in a variety of pathophysiological processes. It has been reported that the pathological process of diabetic cardiovascular diseases (DVD) is closely associated with the activation of ferroptosis. Due to the long-term hyperglycemic environment in diabetic patients, vascular endothelial cells (VECs) are susceptible to ferroptosis, ultimately contributing to vascular dysfunction. Therefore, the development of inhibitors targeting ferroptosis is of great significance for the prevention and treatment of diabetic vascular complications. This review systematically expounds the latest research progress of the molecular mechanism of ferroptosis, and discusses its role in DVD. In addition, this review also comprehensively summarizes the latest advances in the synthesis and application of drugs and specific inhibitors targeting the ferroptosis pathway for disease treatment, thereby providing new therapeutic strategies for DVD.

Background: Histone deacetylases (HDAC) are essential epigenetic enzymes that modulate the remodeling of chromatin and transcriptional activity. Overexpression of HDAC has been associated with tumorigenesis, angiogenesis, metastasis, and therapeutic resistance.

Methods: A systematic survey (2008-2025) evaluated the design, mechanism, and structure-activity relationships (SAR) of azole-based hydroxamic acid (ABHA) derivatives as histone deacetylase inhibitors (HDACIs).

Results: ABHAs containing 1,3,4-oxadiazole, pyrazole, imidazole, triazole, indazole, thiadiazole, etc. Heterocyclic scaffolds show significant zinc-binding affinity, enhanced pharmacokinetics, and isoform-selective inhibition. Subtle structural variations in heteroaryl substituents, linker architecture, and hydroxamate coordination significantly modulate enzyme selectivity and cytotoxic efficacy.

Conclusion: ABHA hybrids provide versatile scaffolds with diverse activity for the rational development of next-generation, isoform-selective HDACIs with enhanced potency and therapeutic promise in anticancer drug design.

Aims: A synthesis of four silver(I) complexes was conducted, and they were evaluated for their antimicrobial properties and their ability to inhibit the formation of biofilms. Additionally, their binding affinities to DNA and BSA were investigated.

Materials & methods: The complexes, chloro[1-isopropyl-3-(3-methylbenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) (2a), chloro[1-isopropyl-3-(3-chlorobenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) (2b), chloro[1-methallyl-3-(3-methybenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) (2c) and chloro[1-methallyl-3-(3-chlorobenzyl)-5,6-dimethylbenzimidazole-2-ylidene]silver(I) (2d) were prepared in 82-84% yields and fully characterized. The biological properties of both ligands and complexes were evaluated in vitro against S.aureus, E.faecalis, E.coli, A.baumannii, C.albicans, DNA and BSA.

Results and conclusions: The complexes 2a-d exhibited a significant inhibitory effect on diverse bacterial biofilms, with percentages ranging from 73.6% to 80.3% for S.aureus, 69.5% to 85.9% for E.faecalis, 76.9% to 88.6% for E.coli, 75.9% to 84.6% for A.baumannii and 70.1% to 82.3% for C.albicans. The most significant activities were observed with complex 2b at 8.5 µM. It was observed that silver(I) complexes exhibited more effective binding to DNA (4.92 × 10³ for 2a), while NHC precursors displayed a higher binding affinity for BSA (5.52 × 10⁴ with 1-isopropyl-3-(3-methylbenzyl)-5,6-dimethylbenzimidazole chloride). While the precursors of ligands exhibited significant toxicity at their highest MIC concentrations, the complexes demonstrated minimal toxicity.

Cancer remains an incessantly rising cause of mortality worldwide, tempting millions of lives each year and posing a significant global health challenge. Available treatment modalities, including chemotherapy, have been associated with limited scope with severe side effects and complexities, underscoring the imperative need for more efficient and safe curative strategies. In this context, the rational design of multitargeted anticancer agents has gained momentum, aiming to enhance therapeutic outcomes while reducing systemic toxicity. The purine scaffold, a core structural motif found in essential biomolecules, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD), has emerged as a promising pharmacophore in anticancer drug discovery. Notably, several synthetic purine analogues have received clinical approval owing to their potent anticancer activity, particularly when integrated with diverse heterocyclic frameworks. This review comprehensively summarizes the advances made over the past decade in the development of purine-based hybrid molecules, highlighting their mechanistic roles in overcoming drug resistance and targeting multiple oncogenic pathways. The insights presented herein underscore the versatility and therapeutic relevance of purine-based scaffolds and aim to guide future efforts in the rational design and development of drug-resistant and safer anticancer agents.

Diabetes mellitus develops because of the disturbance in carbohydrate metabolism. The therapeutic goal for antidiabetic medications is to manage blood glucose level and to prevent hyperglycemia-associated complications. α-Glucosidase inhibitors represent one of the widely used oral hypoglycemics. This review highlights the potential of 1,2,4-triazole-containing synthetic molecules as antidiabetic agents, particularly focusing on their α-glucosidase inhibitory activity. It argues the significance of targeting α-glucosidase in managing type 2 diabetes and presents recent synthetic approaches for synthesizing 1,2,4-triazole derivatives. The mechanisms of action, SAR analysis, and docking insights are summarized for various reported 1,2,4-triazoles between 2020 and 2025. A comparative analysis was conducted to identify the most effective methodology and the best starting material for the synthesis of this class. Relative potencies and drug likeness characteristics of the reviewed candidates were also evaluated to identify whether one deserves forwarding to pre-clinical and clinical assessments. Many of these derivatives exhibited potent α-glucosidase enzyme inhibition, often outperforming standard marketed drugs like Acarbose. The review paves the way for medicinal chemists to develop new 1,2,4-triazole-incorporating molecular entities to build safe and effective agents for diabetes treatment.

Aims: This study aimed to evaluate the α-glucosidase inhibitory potential of newly synthesized aurone derivatives (1-14) using an integrated experimental and computational strategy, with emphasis on their antidiabetic potential.

Materials and methods: The compounds were evaluated through in vitro α-glucosidase inhibition and enzyme kinetic assays, along with in vivo studies to assess postprandial glucose control. Molecular docking, MM-GBSA calculations, and molecular dynamics (MD) simulations were performed to analyze interactions with diabetic targets (PDB IDs: 5NN4 and 6KK1). Furthermore, in silico ADME profiling and density functional theory (DFT) analyses were conducted to predict pharmacokinetic properties, drug-likeness, and electronic behavior.

Results: Several aurone derivatives exhibited strong α-glucosidase inhibition, surpassing standard drugs. Kinetic studies revealed a competitive inhibition mechanism, and in vivo evaluations confirmed their glucose-lowering effects - the first such report for aurones. Computational analyses indicated stable enzyme - ligand complexes with favorable binding affinities and ADME features. DFT results supported the observed structure - activity relationships and highlighted key electronic attributes influencing activity.

Conclusions: This comprehensive study identifies aurones as potent α-glucosidase inhibitors with significant therapeutic potential, providing a strong foundation for further development of aurone-based antidiabetic agents.

The development of soluble epoxide hydrolase (sEH) inhibitors has emerged as a promising therapeutic strategy, yet progress has been constrained by structural similarity and suboptimal pharmacokinetic profiles. While numerous synthetic and natural product-derived inhibitors demonstrate potent pharmacological activity, their clinical translation has been hampered by recurring limitations including poor solubility, low AUC, CYP inhibition, and hERG toxicity. This review critically evaluates recent breakthroughs in scaffold diversification and rational design approaches that overcome these limitations. We highlight innovative synthetic methodologies, structure-activity relationship insights, and novel chemotypes that expand the chemical space beyond conventional urea-based scaffolds. Furthermore, we discuss emerging therapeutic applications enabled by these advanced inhibitors, providing a strategic roadmap for next-generation sEH-targeted drug discovery.

The triazolopyrazine scaffold is characterized by fused triazole and pyrazine rings. It represents a highly versatile, nitrogen-rich heterocyclic framework extensively explored as a prominent scaffold that is of greater importance for developing novel drugs with various biological activities because they may present several structural alterations with identical numbers of carbon and nitrogen atoms. The triazolopyrazine scaffold has broad-spectrum biological activities, including antimalarial, anticancer, antidiabetic, antimicrobial, antifungal, antiviral, and neurological activity. As a result, numerous investigators have synthesized these compounds as target structures and assessed their biological activities. Its broad biological profile has always been a subject of interest, attracting researchers to investigate the distinctive features of this skeleton. In recent years, remarkable progress has been made in the medicinal chemistry of triazolopyrazine-based derivatives. The current review aims to provide research progress on triazolopyrazine hybrids, including structure-activity relationship (SAR) and target interaction analysis, which will pave the way for the design and development of new, novel target-selective triazolopyrazine derivatives as promising agents. This versatile and structurally unique framework of triazolopyrazine scaffold will benefit researchers and medicinal chemists engaged in exploring the triazolopyrazine scaffold as a future lead for drug design and discovery.