Current topics in medicinal chemistry最新文献

Genistein (GEN), a phytoestrogen primarily sourced from soy plants, is recognized for its anticancer properties attributed to its roles as a tyrosine kinase inhibitor, an estrogen receptor agonist, and its influence on various cancer hallmarks by modulating diverse signaling pathways. Recent research has highlighted the considerable potential of GEN in combating drug resistance in cancer cells. This attribute of GEN has been demonstrated by its capacity to modulate tyrosine kinases such as HER2, HER3, and EGFR which are implicated in tumorigenesis, as well as prosurvival signaling pathways including NF-κB and Akt/mTOR. Moreover, GEN impacts drug accumulation, AR-driven transcriptional regulation, ER signaling, and various genes that are involved in autophagy, pro/anti-apoptosis, DNA methylation, and histone acetylation. Further, GEN demonstrated efficacy in combinatorial therapy with various standard anticancer agents like 5-FU, cetuximab, cisplatin, clofarabine, doxorubicin, tamoxifen, TRAIL, trastuzumab, and other agents with anticancer activities such as capsaicin, curcumin, daidzein, lycopene, resveratrol, sulforaphane, etc., across a spectrum of cancers including the cancers of bone, brain, breast, cervix, colorectal, endometrium, esophagus, head and neck, leukemia, liver, lung, ovary, pancreas and stomach. Thus, further clinical validation of these potential combinations involving GEN is warranted to confirm the preclinical findings.

Background: This review is delving into determining the content and significance of hypericin, a pharmacologically important constituent commonly known as St. John's Wort (SJW). The paper explores the rich history of Hypericin's traditional use in alternative medicine and the recent surge in scientific interest surrounding its bioactive properties.

Objective: This review aims to comprehensively analyse the therapeutic potentials of hypericin, focusing on its chemistry, extraction, sources, stability, pharmacokinetics, safety profile, and multifunctional applications in drug and medicinal fields as well as advancements in Bioengineering Approaches for Enhanced Hypericin Delivery.

Methods: We performed a non-systematic search of journals. Literature using computerized methods was conducted, utilizing databases such as Medline (PubMed), ChemSciFinder, China National Knowledge Infrastructure (CNKI) and Scirus Library. To effectively identify the most important and relevant research articles, scientific studies, clinical studies and review articles on hypericin were searched using different keywords: "Hypericum", "traditional use", "phytochemistry", "pharmacology", "drug delivery" and "bioactivity". Thus, articles available from 1984 to 2024 were analyzed and collected. The selection process for the review primarily considered the originality of the paper and its clinical applications.

Results: Although hypericin is not a novel compound within the research community, it is gaining renewed recognition and showing great effectiveness as a promising agent in the field of medical diagnostics and has promising applications as a therapeutic.

Conclusion: Here, our current comprehensive review of hypericin, its potential and its activities is intended to contribute to this ongoing process actively. Overall, this review provided theoretical direction for future hypericin research. Future studies should, therefore, focus further on the pharmacological processes, pharmacokinetics, and chemistry of hypericin and hypericin-based drug delivery systems. Our most recent overview of hypericin's functions and potentials is meant to aid in this process.

Artemisinin and its semisynthetic derivatives are a group of bioactive chemicals obtained mostly from the extracts of Artemisia species that exert a significant amount of antimalarial activity while remaining relatively safe and tolerable. However, their effectiveness is not limited to malaria; it extends to a variety of human infectious diseases. Mostly the mode of action includes the generation of free radicals by breaking the endoperoxide link in its molecular structure, which facilitates the eradication of microbial species. Artemisinins are found to inhibit bacterial, viral, protozoal, helminth, and fungal infections. Their derivatives, like artemisone, a reversible inhibitor, target the viral replication cycle, and artesunate suppresses EBV infection by inhibiting the production of early EBV proteins. They were also found to be highly effective against Helicobacter pylori and Mycobacterium tuberculosis by generating peroxides in a time and concentrationdependent way. Other derivatives, such as artesunate, artemether, and arteether, have also shown antimicrobial activity that can be administered orally, rectally, intramuscularly, or intravenously. This review aims to provide a complete update on the antimicrobial applications of Artemisinin and its semi-synthetic derivatives, as well as derived dimers/trimers. The paper reflects a significant potential for the discovery of novel Artemisinin medications that can be used as supplementary treatments for various diseases. However, further translational and experimental research is required for optimization and the establishment of pharmacokinetic profiles. In addition, health authorities are also required to regulate the present Artemisinins and newly discovered derivatives to ensure their long-term effectiveness in the worldwide fight against antibiotic resistance.

Background: The TLR4 (Toll-like receptor 4)/MD2 (Myeloid differentiation protein-2) is a crucial target for developing novel anti-inflammatory drugs. Nevertheless, current inhibitors often have significant adverse effects, necessitating the discovery of safer alternatives.

Objective: The investigation aims to identify novel TLR4/MD2 inhibitors with potential antiinflammatory activity using machine learning and virtual screening technology.

Methods: A machine-learning model was created using the MACCS (Molecular ACCess Systems) key fingerprint. Subsequently, virtual screening and molecular docking were used to evaluate candidate compounds' binding free energy to the TLR4/MD2 complex. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction was used to assess the druggable properties of compounds. The most promising compound, T19093, was considered for molecular dynamic simulation. Finally, the anti-inflammatory efficacy of T19093 was further validated using LPS-treated THP-1 cells.

Results: T19093, a polyphenolic compound isolated from the Gnaphalium plant genus, showed strong binding to key residues of the TLR4/MD2 complex, with a docking score of -11.29 kcal/mol. Furthermore, ADMET predicted that T19093 has good pharmacokinetic properties and balanced physicochemical properties. Moreover, molecular dynamics simulation confirmed stable binding between T19093 and TLR4/MD2 complex. Finally, it was found that T19093 alleviated LPSinduced inflammatory response by inhibiting the activation of TLR4/MD2 downstream signaling pathways and disrupting the TLR4/MD2 interaction.

Conclusion: T19093 was discovered as a potential novel TLR4/MD2 inhibitor using machine learning and virtual screening techniques and showed potent anti-inflammatory activity, which could provide a new therapeutic alternative for the treatment of inflammation-related diseases.

Diosmetin, also known as 3´, 5, 7-trihydroxy-4´-methoxyflavone, is a bioflavonoid that can be found in several food sources. These include mainly citrus fruits and plants, such as Rosmarinus officinalis, Citrus sinensis, Galium verum, and Rosa agrestis. It has been shown that diosmetin has pharmacological actions that include neuroprotective, antioxidant, and anticancer properties. The objective of this manuscript is to provide a comprehensive review of the pharmacological, pharmacokinetic, and toxicological profile of diosmetin. The information has been collected from several research papers found in various databases, including Web of Science, Pubmed, Scopus, and ScienceDirect. Diosmetin has the potential to reduce inflammation, and it can also improve vascular functions and protect against oxidative stress, both of which are essential for the prevention and management of several diseases.

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.