Current topics in medicinal chemistry最新文献

Introduction: Currently, there are pharmacological treatments for type 2 diabetes (T2D), but these are ineffective. Quercetin is a flavonoid with antidiabetic properties.

Objective: This research aimed to identify the molecular mechanism of Quercetin in T2D from network pharmacology.

Methods: We obtained T2D-related genes from MalaCards and DisGeNET, while potential targets for Quercetin were sourced from SwissTargetPrediction and Comparative Toxicogenomics databases. The overlapping genes were identified and analyzed using ShinyGO 0.77. Subsequently, we constructed a protein-protein interaction network using Cytoscape, conducted molecular docking analyses with SwissDock, and validated the results through molecular dynamics simulation in GROMACS.

Results: Quercetin is involved in apoptotic processes and in the regulation of insulin activity, estrogen, prolactin and EGFR receptor. The key driver genes AKT1, GSK3B, SRC, IGF1R, MMP9, ESR2, PIK3R1, and MMP2 showed high concordance in the molecular docking study, and molecular dynamics showed stability between Quercetin and ESR2 and PIK3R1.

Conclusions: Our work helps to identify the molecular mechanism and antidiabetic effect of quercetin, which needs to be studied experimentally.

Introduction: The persistent drug resistance observed in lung cancer necessitates innovative strategies to improve therapeutic outcomes. This review investigates the potential of combining metformin (Met) and cisplatin (Cis) to overcome drug resistance and enhance treatment efficacy. Cis's limitations, including drug resistance and adverse effects, coupled with Met's established safety profile, form the backdrop for this exploration.

Methods: Systematic literature searches across major databases identified relevant studies exploring the synergistic effects of Met and Cis in the context of drug-resistant lung cancer. Data extraction encompassed diverse facets, including treatment protocols, cellular responses, and mechanistic insights. The synthesis of these findings sheds light on the potential of this combination therapy to combat drug resistance.

Results: Numerous in vitro and in vivo studies have demonstrated the ability of the Met + Cis combination to sensitize drug-resistant lung cancer cells. The co-treatment consistently showed enhanced inhibition of cell proliferation, elevated apoptosis rates, and attenuated migration and invasion capabilities compared to monotherapies. Mechanistically, Met's modulatory effect on key pathways, such as AMPK-mTOR and ROS-mediated signaling, appears to underlie its ability to counter drug resistance.

Conclusion: The Met + Cis combination holds promise as an innovative strategy to counter drug resistance in lung cancer. By harnessing the synergistic effects of these agents, combination therapy offers a novel approach to enhance treatment efficacy and mitigate the challenges posed by drug-resistant lung cancer. Although further clinical validation is required, the Met + Cis synergy represents a promising avenue in the pursuit of improved lung cancer therapy outcomes.

Introduction: CCN6/WISP3 is a member of the CCN adipokines family that can exert multiple effects on metabolic pathways. So far, the function of CCN6 in the pathogenesis of NAFLD has not been known well. Hence, we aimed to examine CCN6 serum levels in patients with NAFLD compared to healthy individuals and its association with some risk factors for the first time.

Method: This case-control study measured serum levels of CCN6, TNF-α, IL-6, adiponectin, and fasting insulin using ELISA kits in 88 NAFLD patients and 88 controls. In addition, other biochemical variables, including AST, ALT, lipid profiles, and FBG, were determined using an Auto analyzer instrument.

Results: A remarkable decrease in CCN6 levels was found in the NAFLD patients (1501.9543 ± 483.414 pg/ml) compared to the healthy group (1899.4856 ± 559.704 pg/ml, P < 0.001). In NAFLD patients, a negatively notable correlation was observed between CCN6 and the levels of insulin (r = -0.278, P = 0.011), HOMA-IR (r = -0.268, P = 0.014), as well as TNF-α (r = -0.343, P = 0.001). A remarkable association was found between CCN6 and the risk factor of NAFLD in the adjusted model for gender, age, and BMI with OR = 0.867 (95% CI, [0.806-0.931], P < 0.001).

Conclusion: Our findings showed a significant reduction in CCN6 levels in the NAFLD patients compared to the healthy group, as well as the developing risk of NAFLD enhanced with the decrease of CCN6 levels.

Background: Recent advancements in the synthesis of novel heterocyclic compounds, particularly oxadiazole derivatives, have garnered significant interest due to their broad pharmacological activities. Despite the oxadiazole ring being a relatively small structure, its derivatives have shown considerable therapeutic potential across a range of diseases. These compounds have been explored for a variety of biological effects, including anti-inflammatory, anticonvulsant, hypoglycemic, antitubercular, anxiolytic, antimicrobial, antitumor, and anticancer properties. The growing issue of drug resistance has further fueled research into the therapeutic promise of oxadiazolebased compounds, particularly for their ability to target resistant diseases.

Objective: This review aims to highlight the pharmacological profiles of oxadiazole derivatives, with a focus on how structural modifications can enhance their activity against specific therapeutic targets. Additionally, the review seeks to explore strategies for overcoming resistance mechanisms associated with these compounds, underscoring their potential in addressing emerging drugresistant diseases.

Conclusion: Oxadiazole derivatives represent a promising class of compounds with significant therapeutic potential, particularly in the face of increasing drug resistance. Their diverse pharmacological activities and ability to be structurally optimized for specific therapeutic targets position them as valuable candidates for further research. Continued exploration of oxadiazole derivatives, with an emphasis on overcoming resistance, may lead to the development of novel treatments for a variety of challenging diseases.

Background: Drug-induced hepatotoxicity is a major concern and is caused by all classes of medications, indicating a key area of research. Antitubercular drugs have a beneficial effect but cause hepatotoxicity on prolonged use.

Aim: The present work aimed to investigate the role of rifampicin-induced hepatic damage and the effect of Cliv-92 on rifampicin-induced alteration in rats.

Methods: Rats were administered with rifampicin, Cliv-92, and silymarin (standard) orally in 0.5% carboxymethyl cellulose (CMC) suspension, in doses of 100 mg/kg, once daily for fourteen days, one hour before the administration of rifampicin. Control animals were treated with 0.5% CMC. On the 14th day, 1hr after the last drug administration, tissue was collected, homogenized, and various parameters, viz. SOD, CAT, GPX, and cytochromes, were estimated from rat liver supernatant and compared with the control group. Blood serum parameters were also measured. Simultaneously, antioxidant activity and in silico studies were performed. The constituent isoforms of Cliv-92 and silymarin and their metabolites were analyzed for different pharmacokinetic characteristics. Silymarin was used as a standard drug.

Result: The result of the study suggests that the hepatoprotective potential of Cliv-92 is due to its antioxidant property and inhibitory effect on hepatoproteins, cytochromes (CPY450). An in-silico finding validates the safety profile of Cliv-92, its metabolites, and the standard drug silymarin and also explains that the drug is non-mutagenic.

Conclusion: The result of this study indicated that both Cliv-92 and silymarin could be used to avoid drug-induced overload and hepatic damage.

The escalating growth and global dissemination of antimicrobial resistance underscore the urgency for the discovery of innovative antimicrobial agents. Antibacterial Peptides (AMPs) have emerged as promising candidates, distinctly outperforming conventional antibiotics due to their mitigated propensity for resistance development, expansive antibiofilm activity, and capacity to favorably modulate host immune responses. Consequently, AMPs have garnered significant attention in medical research circles and are anticipated to serve as novel therapeutic alternatives in combating microbial infections, particularly those involving drug-resistant bacteria, thereby inaugurating a novel paradigm in treatment strategies. This comprehensive review delves into the intricate structural and physicochemical attributes of AMPs, providing a concise overview. It further examines the advancements and anticipated clinical trajectories of AMP research, with a pivotal focus on elucidating their antimicrobial mechanisms and the intricate interplay between structure and activity. The aim of this review is twofold: firstly, to enhance the scientific community's comprehension of the antimicrobial mechanisms and Structure-Activity Relationships (SAR) across all classes of AMPs; secondly, to address existing research gaps in the SAR of AMPs, thereby laying a solid foundation for future research endeavors and facilitating the development of these promising therapeutic agents.

Cancer epidemiological studies highlight the critical need for identifying better treatment options against cancer. Plants have been widely studied to obtain their efficacy as potent therapeutic agents to treat several diseases, including cancer. Interestingly, some phytocompounds, such as flavonoids, terpenoids, alkaloids, phenolics, and organosulphur compounds [OSCs], have been demonstrating their potential role in combating several pathologies, including the second most devasting disease, cancer, which contributes a significant portion of annual mortality cases. Several in vitro, in vivo, and in silico investigations have recently established remarkable properties of phytocompounds such as antioxidant effects, induction of apoptosis, inhibition of metastasis, autophagy modulation, cell cycle regulation, and chemosensitization that lead to cancer suppression. This underscores the great potential of phytocompounds to contribute as an effective anticancerous drug for the prevention of cancer cases and advancement in cancer research. Therefore, comprehending the complicated mechanism involved in the anticancerous effects of phytocompounds against several carcinomas is crucial to establishing novel therapeutic strategies. Thus, this review tends to summarize the involvement of the most promising classes of phytompounds in cancer management and highlights several clinical trial data that demonstrate significant results in managing diverse carcinomas.

A neurohormone with strong central nervous system activity, melatonin plays a role in regulating circadian rhythms. It affects practically all tissues and organs and has a broad functional repertoire. It is primarily employed as a dietary supplement; melatonin aids in sleep regulation and the re-establishment of arousal cycles. Despite having very low toxicity, melatonin's tissue availability is constrained by pharmacokinetic problems such as poor oral bioavailability and a brief half-life. The synthesis and medicinal applications of melatonin and its derivatives are the main focus of this review study. Melatonin is considered as a beneficial agent suitable for safely treating and preventing various health conditions. This review covers synthesis approaches and pharmacological applications of melatonin and its derivatives published from the 1990s to 2024. The latest development in several studies involves the concurrent administration of melatonin with other drugs to enhance therapeutic effectiveness and mitigate adverse effects. Hybrid ligands, such as melatonin-tamoxifen and melatonin-tacrine derivatives are combined to give distinct effects. This review highlights the importance of continued research into melatonin and its derivatives, paving the way for developing novel and more potent therapeutic agents.

Introduction/objective: The increasing resistance of pathogens to antibiotics poses a major public health challenge. This study aims to develop an innovative approach to combat this resistance by exploring synergies between standard antibiotics and marine metabolites.

Methods: The methodology combines disk diffusion testing and mixture design to assess the antimicrobial efficacy of the combinations.

Results: The results demonstrate promising synergies between carotenoids, polyphenols, and alkaloids with standard antibiotics, offering potential targeted use in the fight against clinical multidrug- resistant bacteria. Specifically, Gram-negative bacteria (BGN) showed increased resistance to antibiotics such as amoxicillin-clavulanic acid (AMC), ceftazidime, cefotaxime, tetracycline, and cefazolin. These antibiotics, when combined with marine compounds, exhibited substantial inhibitory effects against specific isolates, circumventing antibiotic resistance mechanisms. Similarly, substantial synergies were observed in Gram-positive bacteria. Leveraging advanced algorithms such as multi-objective optimization, notably the NSGA-II algorithm, we accurately predicted minimum inhibitory concentrations (MICs) against clinically resistant bacterial isolates. Optimal conditions against Escherichia coli, characterized by carotenoids = 0.6335, total polyphenols = 0, indole alkaloids = 0.1723, and AMC = 0.1941, yielded a predicted MIC of 41.1126 mg/L, closely mirroring the experimental MIC of 41.66 ± 0.18 mg/L. Similarly, for Staphylococcus aureus, optimal conditions produced a predicted MIC of 30.8304 mg/L, closely aligning with the experimental MIC of 30.69 ± 1.80 mg/L.

Conclusion: The consistent and reliable predictions for bacterial strains affirmed the robustness of the applied methodology. These results not only pave the way for further exploration but also offer valuable insights for optimizing pharmaceutical and medical interventions, presenting innovative avenues for combating antibiotic-resistant bacterial infections.

Anti-angiogenic therapy represents a promising approach to cancer treatment by targeting the vascular support systems of tumors rather than the tumor cells themselves. Antiangiogenic agents face numerous obstacles that impede their efficacy, notwithstanding their potential: mechanistic complexity, toxicity, resistance, and the lack of validated predictive biomarkers. Resistance mechanisms may encompass genetic modifications, alternative angiogenic pathways, or the recruitment of cells derived from bone marrow. This work examines present problems and approaches to overcome resistance against anti-angiogenic treatment. Treatment response is predicted by biomarker-guided therapy; patterns of circulating endothelial cells, IL-8 levels, and VEGFR expression indicate possible therapeutic monitoring value. Multi-targeted approaches including drugs that block VEGFR, PDGFR, FGFR, and c-MET concurrently have shown more efficacy than single- pathway inhibition. Additional research indicates that combining treatments has positive results. Combining anti-angiogenic agents with cancer vaccines increases immune responses and tumour regulation. Combining radiotherapy with chemotherapy increases drug delivery and efficacy utilizing vascular normalisation. Techniques based on nanotechnology such as gold nanoparticles and carbon-based materials may enhance medicinal efficacy and delivery. These results reveal that to overcome resistance mechanisms and enhance patient outcomes anti-angiogenic therapy must combine focused therapies with precision medicine approaches.