Current topics in medicinal chemistry最新文献

Cancer is a multifaceted disease with high mortality rates, and current treatments face challenges such as chemoresistance and tumor adaptation. Since Virchow reported the first case of cancer-related chronic inflammation, numerous clinical and epidemiological studies have indicated that around 15-20% of malignant tumors are caused by inflammation. Cyclooxygenase-2 (COX-2), which is the key enzyme in inflammation, has been implicated in tumorigenesis through various mechanisms, including promoting angiogenesis, inhibiting apoptosis, and enhancing the invasiveness of cancer cells. Moreover, COX inhibitors have demonstrated a substantial reduction in death rates associated with esophageal and colon cancer. In this context, targeting COX-2 is an effective strategy for cancer prevention and treatment. This review focuses on the analysis of studies conducted between 2014 and 2024, which evaluate the structure-activity relationship of molecules intended to exhibit cytotoxic activity through COX inhibition. The studies followed both classical and non-classical COX-2 selective drug design strategies. While some focused on the classical approach, utilizing diaryl heterocyclic structures, others explored non-classical designs with a cyclic central scaffold and a linear core. Additionally, several manuscripts employed well-known COX inhibitors, including licofelone, indomethacin, naproxen, tolfenamate, celecoxib, flumizole, and ketoprofen, as starting points for further derivatization and optimization. Cytotoxic activity was evaluated using various cell lines, including MCF- 7, HCT-116, and A549, through assays such as MTT, CellTiter, and MTS. Additionally, studies examined the relationship between COX-2 inhibition and key cancer pathways, including apoptosis and the involvement of enzymes like HDAC, EGFR, and topoisomerase. The majority of studies reported promising cytotoxic activity in COX-2 selective inhibitors. Compounds synthesized with diphenyl heterocyclic scaffolds exhibited enhanced COX-2 selectivity and anticancer efficacy. In particular, derivatives in studies 9, 16, and 24 demonstrated significant activity comparable to standard drugs like celecoxib and doxorubicin. However, only a few studies indicated a weak correlation between COX-2 inhibition and cytotoxicity, suggesting the need for further investigation into other cancer-related mechanisms. This review highlights the potential of COX-2 selective inhibitors in anticancer drug development. The findings support the development of selective COX-2 inhibitors with diverse chemical structures as a promising strategy for cancer therapy.

Introduction: Ginseng, a perennial herb belonging to the Araliaceae family, is renowned for its traditional and folk uses. The Panax ginseng C.A. Meyer species is predominantly found in Asian countries, including Japan, China, and Korea.

Materials and methods: This manuscript offers valuable insights into the cultivation, collection, morphology, phytochemistry, pharmacological properties, and clinical studies of Ginseng. The data was meticulously gathered from diverse electronic resources, such as PubMed, Scopus, Science Direct, and Web of Science, spanning from 1963 to 2023.

Results: Ginseng contains various bioactive components, including carbohydrates, polyacetylenic alcohols, polysaccharides, ginsenosides, peptides, vitamins, and fatty acids. The biological attributes of ginsenosides, which include anti-diabetic, anti-cancer, anti-oxidant, and anti-inflammatory activities, render them especially remarkable.

Conclusion: This manuscript comprehensively explores the versatile therapeutic applications of ginseng in the treatment of various types of cancers.

Objectives: This systematic review was conducted to evaluate the applicability of the envelope (E) protein in the diagnosis of arboviruses.

Methods: This review was performed in accordance with the PRISMA statement. Five databases were explored (PubMed, Web of Science, Scopus, EMBASE, and IEDB). The inclusion and exclusion criteria were applied to study eligibility. After data extraction, the risk of bias and evidence certainty were evaluated according to QUADAS and GRADE assessments, respectively.

Results: Eleven studies were included. A total of 11 studies were included in the review. ELISA was the most frequently utilized technique, with two studies employing it for antigen detection and nine for antibodies. The E protein was used as a whole protein, heterologous protein, and peptides. The diagnostic metrics were enhanced by optimizations on techniques, such as antibody capture, competitors, and nanosensors. Monoclonal antibodies showed improved specificity, including in coinfected samples. Seven studies demonstrated a minimal risk of bias, and the evidence certainty was considered moderate for dengue diagnosis.

Conclusions: The E protein was successfully employed in different immunological assays with large-scale strategies, enhancing the applicability potential for differential arboviruses' diagnosis. Furthermore, both the antigen design and the implementation of innovative methodologies will have a substantial impact on the quality of the new tests. The PROSPERO protocol related to this work: CRD42021265243.

Introduction: Heterogeneous Acute Myeloid Leukemia (AML) causes substantial worldwide morbidity and death. AML is characterized by excessive proliferation of immature myeloid cells in the bone marrow and impaired apoptotic regulator expression.

Method: B-Cell Lymphoma 2 (BCL-2), an anti-apoptotic protein overexpressed in AML, promotes leukemic cell survival and chemoresistance. Thus, reducing BCL-2 may treat AML. Anticancer activities are found in Aloe barbadensis Miller (Aloe vera). Thus, this work used molecular modeling to assess Aloe vera bioactive chemicals as BCL-2 inhibitors. Molecular docking simulation showed that all identified Aloe vera phytocompounds have strong BCL-2 binding affinities (-6.7 to -8.7 kcal/mol).

Result: Campesterol and α-tocopherol were identified as promising compounds for BCL-2 inhibitor research based on their drug-likeness, pharmacokinetics, and toxicity profiles. The stability and conformational of the BCL-2-compound complexes showed that the compounds were stable in BCL-2's binding pocket.

Conclusion: Campesterol and α-tocopherol are promising BCL-2 inhibitors that might become effective anti-leukemic therapies with additional in vitro and in vivo research.

Cardiovascular disorders develop the highest rates of mortality and morbidity worldwide, emphasizing the need for novel pharmacotherapies. The Chinese medicinal plant S. baicalensis has a number of major active components, one of which is called baicalin. According to emerging research, baicalin reduces chronic inflammation, immunological imbalance, lipid metabolism, apoptosis, and oxidative stress. Baicalin improves endothelial function and protects the cardiovascular system from oxidative stress-induced cell injury by scavenging free radicals and inhibiting xanthine oxidase. Therefore, it helps prevent CVD such as hypertension, atherosclerosis, and cardiac arrest. In this review, the therapeutic effects of baicalein are discussed in relation to both the prevention and management of cardiovascular diseases.

Non-fused pyrimidine scaffold is a significant component for designing new drugs. The review emphasizes the pharmacological importance of non-fused pyrimidine-containing moieties based on the broad spectrum of activities such as antiprotozoal, antibacterial, antimycobacterial, anticancer, anti-inflammatory activity, and CNS depressant. Pyrimidine derivatives are fascinating entities that display biological activities for the treatment of cancer. It also highlights the tendency of non-fused pyrimidine derivatives to suppress cell growth by obstructing the activity of VCP, CDK-2, EGFR, ATR, EphB4 & EphA2, PDGF as well as inhibitory action towards different cell lines such as MCF-7, HeLa, NCI/ADR-RES, NCIH23, HOP-92, HCT-116, OV-3, MOLT-4, PC-3, MDA-MB-231, MALME-3M, K562 and Bcr-Abl. The review details the importance of morpholine, piperidine, and pyrrolidine ring substitutions on pyrimidine moiety as well as the role of H-bonding and amino linkage along with antibacterial activity due to the presence of pleuromutilin and tetrazole molecules. Researchers were motivated to develop and enhance the non-fused pyrimidine scaffold to uncover novel medicines by reading this review article.

Healthy skin is essential for balanced health. Currently, skin diseases are considered a major global health issue, impacting individuals of all ages. Skin conditions can vary broadly, ranging from common issues like acne and eczema to more serious diseases such as psoriasis, melanoma, and other types of skin cancer. In recent years, computational methods have appeared as powerful tools for explaining the lurking mechanisms of skin diseases and the advancement of the discovery regarding updated therapeutics. This review spotlights the notable researches that have been performed in using computational approaches such as virtual screening, molecular modelling, and molecular dynamics simulations to discover potential treatments for dermatological conditions such as eczema, psoriasis, acne vulgaris, skin cancer, and tyrosinase-related disorders. Moreover, using in silico methods, researchers have explored the molecular interactions between cosmetic actives and skin targets, providing insights into the binding affinities, stability, and efficacy of these compounds. This computational exploration allows the identification of potential off-target effects and toxicity profiles, ensuring that only the most promising candidates proceed to clinical testing. In addition, the use of molecular dynamics simulations helps to understand conformational changes and interaction dynamics over time, further refining the selection of effective cosmetic actives. Overall, the integration of computational chemistry into dermo-cosmetic research has immense potential to accelerate the discovery and development of innovative treatments to improve skin health and address dermatological concerns.

Introduction: Hyperpigmentation disorders are caused by excess production of the pigment melanin, catalyzed by the enzyme tyrosinase. Novel tyrosinase inhibitors are needed as therapeutic agents to treat these conditions.

Method: To discover new inhibitors, we performed a virtual screening of the ZINC20 library containing 1.4 billion compounds. An initial filter for drug-likeness, ADMET properties, and synthetic accessibility reduced the library to 10,217 hits. Quantitative structure-activity relationship (QSAR) modeling of this subset predicted nanomolar inhibitory potency for several chemical scaffolds. Comparative molecular docking studies and rigorous binding energy calculations further prioritized four cysteine-containing dipeptide compounds based on predicted strong binding affinity and mode to tyrosinase.

Results: Microsecond-long molecular dynamics simulations provided additional atomistic insights into the stability of inhibitor-enzyme binding interactions. This integrated computational workflow effectively sampled an extremely large chemical space to discover four novel tyrosinase inhibitors with half-maximal inhibitory concentration values below 10 nM.

Conclusion: Overall, this demonstrates the power of virtual screening and multi-faceted computational techniques to accelerate the discovery of potent bioactive ligands from massive compound libraries by efficiently sampling chemical space.

Introduction: The mutual activations of multiple signaling pathways are the key factors in the development and progression of myocardial cell injuries.

Objective: This research aimed to compare the different degrees of myocardial injury after coronary stenting, permanent pacemaker implantations, or cardiac radiofrequency ablation and to investigate the effects of the mutual activation of TNF-α/NF-κB, TLR2/TLR4, and ROS/MDA signaling pathways on myocardial injury in elderly patients after coronary stents or permanent pacemakers or radiofrequency ablation.

Methods: We determined reactive oxygen species (ROS), malondialdehyde (MDA), toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor- α (TNF-α) and high-sensitive cardiac troponin T (hs-cTnT) as a marker of myocardial injury in patients.

Results: The levels of ROS, MDA, TLR2, TLR4, NF-κB, TNF-α, and hs-cTnT were increased in patients with permanent pacemaker implantations when compared to patients with cardiac radiofrequency ablation (P < 0.01) at 6 months and were further increased in patients with coronary stenting compared to patients with cardiac radiofrequency ablation and permanent pacemaker implantations at 6 months, respectively (P < 0.01). This research confirmed that ROS, MDA, TLR2, TLR4, NF-κB, and TNF-α predicted myocardial injury severity.

Conclusion: Oxidative stress (ROS/MDA signaling pathway) may be linked to immune response (TLR2/TLR4 signaling pathway) and pro-inflammatory response (TNF-α/NF-κB signaling pathway) in myocardial injury, and ROS/MDA signaling may play a dominant role.

Aims: The aim of the current study was to explore the anti-diabetic potential of Ochradenus aucheri Boiss (O. aucheri).

Method: All the fractions of O. aucheri were evaluated for α-glucosidase inhibition, followed by bioassay-guided isolation which resulted in a new sesquiterpenoid, as a potential α-glucosidase inhibitor.

Results: The preliminary screening showed that all the fractions including n-hexane (38.0 ± 1.38 μg/mL), dichloromethane (92.6 ± 6.18 μg/mL), ethyl acetate (29.2 ± 0.51 μg/mL) and n-butanol (361.8 ± 5.80 μg/mL) displayed significant α-glucosidase inhibitory activity. The activity-directed fractionation and purification of ethyl acetate fraction led to the isolation of one new sesquiterpenoid, Jardenol (1), and two known metabolites: β-stitosterol-3-O-β-D-glucopyranoside (2) and β-Sitosterol (3). To the best of our knowledge, these metabolites have not been isolated from this plant previously. The structure of the new metabolite 1 was confirmed through 1D and 2D NMR spectroscopy, and MS analysis. Compound 1 showed significant α-glucosidase inhibition with an IC50 value of 138.2 ± 2.43 μg/mL as compared to positive control acarbose (IC50 = 942.0 ± 0.60 μg/mL). Additionally, in-silico docking was employed to predict the binding mechanism of compound 1 in the active site of the target enzyme, α-glucosidase. The docking results suggested that the compound forms strong interactions at the catalytic site of α-glucosidase.

Conclusion: The results of the present study indicated that the newly purified secondary metabolite, Jardenol, can be a promising anti-diabetic compound.