Medicinal Chemistry Research最新文献

Bacterial biofilms are surface-attached communities comprised of slow- or non-replicating bacteria. Transcriptomic responses of bacterial biofilms to anti-biofilm small molecules have been largely unexplored, with existing studies typically involving long treatment periods (>18 h). In this study, we used a halogenated quinoline biofilm-killing agent (RA-HQ-12) to investigate the transcriptional responses of MRSA and S. epidermidis biofilms. Utilizing RT-qPCR, we observed RA-HQ-12 activated iron uptake pathways in both MRSA and S. epidermidis biofilms after 4 h treatment at 1 µM. A time-course analysis further revealed dynamic variation in up- and down-regulation patterns of various target genes (sbnC, isdB, opp1C, ribA, nasE, and crtM), shedding light on the time-dependent dynamics of biofilm responses to RA-HQ-12.

Neglected tropical diseases caused by protozoan parasites such as Leishmania (L.) and Trypanosoma (T.) species pose significant health, social, and economic challenges globally. Current treatments are often toxic, with complex administration routes. Additionally, these drugs are prone to parasite resistance, necessitating the search for novel therapeutic agents. To this end, we initiated a program to investigate the antiparasitic potential of arylidene compounds. In this preliminary study, a small series of 5-benzylidene-2-thiohydantoin esters was synthesised in a multi-step process and evaluated for antitrypanosomatid activity against Leishmania and Trypanosoma species. The in vitro biological evaluation revealed promising leishmanicidal activity against the antimony-resistant L. donovani strain 9515 and L. major strain NIH S, as well as trypanocidal activity against the T. congolense strain IL3000. Most compounds exhibited low cytotoxicity toward mammalian cells, resulting in high selectivity indices. Several early leads against visceral and cutaneous leishmaniasis, with similar potency to the reference drug amphotericin B, were identified (IC₅₀ < 1 µM, SI > 100). For example, A1-13 demonstrated cidal activity in the nanomolar range against intracellular amastigotes of L. donovani (IC₅₀ 0.41 µM, SI 244) and A2-4 against L. major (IC₅₀ 0.49 µM, SI 204). Additionally, A2-5 (IC₅₀ 0.35 µM, SI 452) was identified as an early lead against animal-infective T. congolense trypomastigotes, a causative agent of the cattle wasting disease nagana. Drug-likeness predictions confirmed favourable physicochemical properties with minimal predicted toxicity risks. These findings provide valuable insights into the development of thiohydantoin-based therapeutics for neglected tropical diseases; however, the mechanism of action and in vivo antitrypanosomatid efficacy of the promising early leads should be further determined.

Drug repurposing has evolved as an attractive approach in the search for new therapeutic applications that are shorter in development time and lower in cost. At the core of drug repurposing, the key challenge in this field is the accurate prediction of drug-target interactions (DTIs) and drug-target binding affinities (DTBAs). Various Artificial Intelligence (AI) techniques, including machine learning (ML) and deep learning (DL) methods, have proven to be significant in improving the prediction capability of the DTI and DTBA models. In this review, we provide critical insights into the current state-of-the-art AI methods used for the prediction of DTI and DTBA by highlighting major progress, bottlenecks, and potential future research directions. Classify these approaches according to their algorithmic framework, feature extraction methods, data source, and performance measures, and provide an extensive review of their strengths against limitations. Lastly, the limitations of current AI-assisted DTI and DTBA prediction methods in drug repurposing applications are summarized and highlight possible directions to address those challenges.

Portulaca oleracea L., commonly known as purslane or pigweed, is a fleshy, drought-resistant weed belonging to the family Portulacaceae. It grows worldwide, including regions such as Asia, Europe, China, the Mediterranean, Japan, the U.S., Africa, and Australia. P. oleracea leaves have long been used in traditional cuisine, eaten as a steamed green, added to pickles, tossed in salads, or used to thicken soups. Rich in essential nutrients, this plant is especially valued for its abundant omega-3 fatty acids, which play a vital role in growth, development, and protection against diseases. It also contains diverse bioactive compounds, including flavonoids, carotenoids, monoterpene glycosides, phenolic glycosides, triterpenoids, alkaloids, carbohydrates, proteins, vitamins, minerals, and electrolytes. These bioactive compounds give P. oleracea its diverse medicinal benefits, including antioxidant, heart protective, anti-atherosclerotic, anti-inflammatory, cholesterol-lowering, blood-thinning, glucose regulating and antimicrobial effects. Recent research has also explored using P. oleracea extracts to produce biogenic metallic nanoparticles, opening new possibilities in photocatalysis and advanced medical nanotechnology. This review comprehensively summarizes the updated phytochemical profile and pharmacological activities of purslane extracts, linking traditional knowledge with cutting-edge applications with emphasizing its role as a vital resource for human health.

Cancer is a wound that never heals and is the second leading cause of death worldwide. Ginsenoside Rh2 (G-Rh2) is the main active substance extracted from Panax ginseng c.a. Meyer, has anticancer activity. G-Rh2 can inhibit tumor cell proliferation, migration, invasion, and neovascularization, regulate immune function, and induce apoptosis and cycle blockade in vitro and in vivo. In addition, G-Rh2 can be used as an adjuvant to chemotherapeutic drugs to enhance their anticancer effects and reverse adverse effects. In this study, the anti-tumor mechanism of G-Rh2 was organized and reviewed by reviewing relevant reports in recent years to provide guidance for the application of G-Rh2 in clinical tumor therapy.

METTL3 and METTL14, key components of the m⁶A writer complex, are frequently overexpressed in various malignancies, including acute myeloid leukemia (AML), where aberrant methylation has been linked to the upregulation of oncogenic transcription. Therefore, targeting the METTL3/METTL14 complex represents a potential therapeutic approach for AML. Although several METTL3 inhibitors have been discovered, their SAM-competitive mode of action often results in reduced cellular potency, prompting interest in alternative strategies such as targeted protein degradation. In this article, we expand upon reported METTL3/METTL14 complex degraders through exploration of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) from multiple exit vectors of UZH2, a reported METTL3 inhibitor. The most potent PROTAC, 4j, demonstrated sub-micromolar degradation potency in MV4.11 cells with DC₅₀ values of 0.44 µM for METTL3 and 0.13 µM for METTL14. Notably, 4j showed enhanced cytotoxicity in MV4.11 cells compared to well-validated METTL3 inhibitors, underscoring the therapeutic potential of targeted degradation of the METTL3/METTL14 complex in AML.

In this work, we designed and synthesized 12 triphenylphosphonium (TPP) conjugates of acetylenated nucleic bases (uracil, thymine) and their analogues (6-methyluracil, quinazoline-2,4-dione) and evaluated their in vitro cytotoxicity against 9 human cancer cell lines M-HeLa, HuTu 80, MCF-7, T 98 G, A 549, DU-145, SK-OV-3, PC-3, A-375 and two lines of normal human cells RPMI 1788 and WI-38. All synthesized TPP-conjugates showed high cytotoxicity (IC₅₀ values in the range of 0.1–7.3 µM) against all used human cancer cell lines. The mechanisms of cytotoxic action were studied for the lead compounds 2c,d, 4c,d which exhibited very high cytotoxicity (IC₅₀ = 0.2–0.3 μM) against PC-3 cancer cells. The flow cytometry method using Annexin V and propidium iodide (PI) has shown that the lead compounds cause apoptosis of PC-3 cells. With the help of flow cytometry using cationic carbocyanine dye JC-1, it was found that the lead compounds cause a significant dose-dependent decrease in the mitochondrial membrane potential of PC-3 cancer cells, that induces apoptosis along the mitochondrial pathway. Significant ROS production in PC-3 cells after their treatment with the lead compounds 2c,d was detected by flow cytometry using CellROX® Deep Red fluorogenic probe. Enzyme-linked immunosorbent assay (ELISA) found that the lead compounds activated apoptosis-initiating caspase-9 and blocked anti-apoptotic Bcl-2 protein in PC-3 cancer cells. This experimental fact was explained by molecular docking.

Wedelia species (the Asteraceae family) are renowned for treating several inflammation-related diseases clinically, such as pertussis and pharyngitis. Plants of the genus contain diverse bioactive metabolites. The review comprehensively describes scientific investigations regarding Wedelia species, comprising phytochemical record, pharmacological value, toxicological evaluation, and nano- and semisynthetic preparations. Four online sources Web of Science, Scopus, Google Scholar, and PubMed have been extensively used in the search for English references. The phytochemical profile of Wedelia species consisted of 290 secondary metabolites, which can be classified as terpenoids, phytosterols, saponins, phenolics, and others. Sesquiterpenoids and ent-kaurane diterpenoids were the major compounds. Wedelia species are also rich in terpenic essential oils. Wedelia constituents have a broad panel of pharmacological activities, such as anticancer, anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antinociceptive, and antiviral activities. It is also useful in applications that protect the neurons, liver, and bones, and aid in wound healing. Bezofuran, wedelolactone, and two major diterpenoids, kaurenoic acid and grandiflorenic acid, are likely the bioactive molecules. Various molecular mechanisms of anti-inflammatory action have been proposed, including the nuclear factor kappa B/mitogen-activated protein kinase (NF-κB/MAPK) signaling pathway. Wedelia extracts were associated with an LD₅₀ value of more than 2000 mg/kg to rats. Nanoformulation and semisynthesis would enhance the pharmacological activities of Wedelia. In vitro and in vivo pharmacological studies for a vast number of Wedelia isolates are encouraged. Developing new formulations with more therapeutic value is expected.

The DPPH radical scavenging, α-glucosidase inhibitory, nitric oxide (NO) inhibitory, and cytotoxic activities of the extracts from fruiting bodies of wood-rot basidiomycete Fulvifomes fastuosus were evaluated in this study. While the CH₂Cl₂ extract was biologically inactive, chromatographic fractionation led to the isolation of two chlorinated hydroquinone derivatives, drosophilin A methyl ether (DAME; 1) and drosophilin A (DA; 2). The EtOAc-partitioned fraction, obtained from the partitioning of the MeOH extract, exhibited strong α-glucosidase and NO inhibitory activities. Further investigation led to the isolation of inoscavin A (3) as the major constituent, along with inoscavin E (4) and polyphenols (5–7). Inoscavin A demonstrated potent α-glucosidase inhibition (IC₅₀ = 3.22 µM), surpassing acarbose by 59-fold, and exhibited non-competitive inhibition kinetics (Kᵢ = 3.25 µM). Molecular docking studies supported an allosteric binding mode. It also displayed favorable drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, including good solubility, high intestinal absorption, low central nervous system (CNS) penetration, and absence of hepatotoxicity. These results suggest that F. fastuosus is a promising source of antidiabetic agents, with inoscavin A as a principle active compound.

Formononetin (FMN), a natural isoflavone with broad biological activity, has emerged as a potential lead molecule as an anticancer agent. In this work, different FMN ester derivatives were synthesized via an acylation reaction (3a-d). The structural characterization and purity of the compounds were confirmed through NMR, HRMS, and HPLC analysis. Among the synthesized derivatives, the 4-Morpholinecarbonyl chloride conjugated FMN (FMN-4Morpho; 3b) demonstrated significantly (p < 0.05) enhanced cytotoxicity against multiple cancer cell lines, including A549, B16F10, and 4T1, while showing no notable toxicity up to 200 μM in non-cancerous L929 fibroblasts and RAW 264.7 macrophages, indicating good biocompatibility. The mechanistic evaluations in A549 and 4T1 cells revealed elevated ROS production, disruption of mitochondrial membrane potential, and increased apoptosis, as revealed by JC-1 and Annexin V-FITC/PI staining. Additionally, FMN-4Morpho suppressed colony formation and cell migration, downregulated cyclin A, cyclin D1, MMP-2, and MMP-9, and upregulated p53 and Bax expression, thereby lowering the Bcl-2/Bax ratio. The findings highlight FMN-4Morpho as a promising therapeutic candidate with improved anticancer efficacy.