Medicinal Chemistry Research最新文献

Free Fatty Acid Receptor-1 (FFAR1) agonists are promising candidates for the treatment of type 2 diabetes mellitus due to their glucose-lowering ability. Previously, we have shown that a benzyloxyphenylpropanoic acid derivative QS-619 (5d) containing a (−)-borneol residue acts as an effective FFAR1 agonist and exerts a hypoglycemic effect in mice. To establish the initial structure-activity relationships (SAR) for this chemotype, with a particular focus on the critical role of the terpene fragment’s stereochemistry, we synthesized a series of its structural analogues with variations in the configuration of stereocenters and the position of substituents in the aromatic rings. The effect of borneol stereochemistry on hypoglycemic activity was studied. The cytotoxicity of the synthesized compounds was evaluated on HepG2 and HEK293T cell lines. The hypoglycemic activity of these compounds was assessed in an oral glucose tolerance test (OGTT) in mice at doses of 15 mg/kg and 30 mg/kg. The most potent hypoglycemic agent identified was compound 5e which bears a (+)-bornyl moiety. It demonstrated a strong effect at both doses, showed no cytotoxicity (CC₅₀ >100 µM), but exhibited acute toxicity at a dose of 1000 mg/kg. Compounds 5f and 5g, containing (−)- and (+)-isobornyl moieties, respectively, showed a less pronounced hypoglycemic effect compared to the bornyl derivatives 5d and 5e. The cyclohexyl derivative 5h was active only at the 30 mg/kg dose. Furthermore, co-administration of an FFAR1 antagonist was found to suppress the hypoglycemic activity of the studied compounds in the OGTT, supporting an FFAR1-mediated mechanism of action.

Pancreatic cancer remains a highly lethal malignancy with limited treatment options. Given the versatile bioactivity of quinazoline derivatives, which are regarded as a promising scaffold for anticancer drug discovery, we designed and synthesized a series of novel quinazoline analogues. Their cytotoxicity was evaluated in three pancreatic cancer cell lines (HPAC, AsPC-1, and MIA PaCa-2), leading to the identification of compound 5a, which exhibited potent effects across all tested cell lines. Further investigation of anticancer activity indicated that 5a significantly inhibited DNA synthesis, clonogenesis, and migration in MIA PaCa-2 cells. Mechanism study revealed that 5a disrupted autophagy, as evidenced by downregulation of Beclin-1 expression and accumulation of LC3B-II and p62, through a mechanism independent of the canonical AMPK-mTOR-ULK1 signaling pathway. This study provides a promising active scaffold for the development of anti-pancreatic cancer agents.

The genus Volkameria, belonging to the family Lamiaceae, comprises flowering plants with a pantropical distribution and a rich diversity of traditional applications and phytochemical compositions. Currently, 13 species are classified under this genus, which were previously categorized under different genera. This review aims to summarize the most up-to-date botanical descriptions, geographical distributions, ethnobotanical uses, phytochemistry, and pharmacological activities of Volkameria plants. Various databases and search engines, such as PubMed, Science Direct, Google Scholar, Sci-finder, Research Gate, online floras, and other published/unpublished resources, were consulted to compile this article. Volkameria species have been extensively used in traditional medicinal practices across different cultures to treat conditions such as fever, malaria, edema, cough, skin diseases, ulcers, inflammation, and rheumatism. Among the 13 accepted species, only four have been phytochemically investigated, with significant research focused on Volkameria inermis. Nearly 145 phytochemicals belonging to various classes, including flavonoids, diterpenoids, triterpenoids, steroids, and phenolic/lignan/iridoid/megastigmane glycosides, have been isolated and reported. Notably, flavonoids, diterpenoids, and triterpenoids have shown significant biological activities. V. glabra, and V. inermis have been studied for their pharmacological properties, such as antioxidant, anti-inflammatory, antimicrobial (including antibacterial, antiviral, antifungal, antimalarial, neuroprotective, anti-motor tics, insecticidal, and antifeedant effects. However, the remaining species require further investigation. Comprehensive studies, including preclinical and clinical trials, are essential to validate the efficacy and safety of these plants for medicinal use.

To develop structurally novel and efficient insecticides, a series of ethylpyridine-containing meta-diamide derivatives were designed and synthesized using cyproflanilide as the lead compound. The core bioactive scaffold was retained while integrating active substructure combination and pharmacophore fusion strategies. All compounds were characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. Preliminary bioassay data showed that some target compounds exhibited good insecticidal activity against Plutella xylostella, Mythimna separata, and Tetranychus cinnabarinus. Particularly, compound 7 g exhibited 100% lethality at a concentration of 1 mg/L against both Plutella xylostella and Mythimna separata; meanwhile, compound 7q achieved complete lethality against Tetranychus cinnabarinus at a concentration of 100 mg/L. Further structure–activity relationship (SAR) analysis based on in vitro efficacy data provided a theoretical foundation for developing next-generation acaricides/insecticides. These findings offer valuable insights for designing novel meta-diamide agrochemicals with enhanced efficacy.

The worldwide spread of antimicrobial resistance (AMR) is a considerable challenge to global health, resulting in a substantial depletion of human and material resources. Conventional antimicrobial agents are often ineffective against contemporary resistant strains, making the identification of novel drug targets a priority in antimicrobial development. Inhibition of the bacterial type II fatty acid synthesis (FAS-II) pathway is recognized as an effective antimicrobial strategy. β-Ketoacyl-ACP synthase III (FabH), a crucial enzyme in the FAS-II, presents potential as a target for next-generation antimicrobial agents. In recent years (2006–2025), research on synthetic small-molecule inhibitors targeting FabH has attracted widespread attention among scientists. However, reviews on FabH inhibitors remain scarce, with reports scattered across the literature. This paper outlines the attributes of FabH in various bacterial species and compiles the currently documented synthetic inhibitors. It examines the inhibitory effects of various core structures on FabH and analyzes the structure-activity relationships of specific compounds, including triazoles, carbazoles, indoles, and pyrazoles, etc. The goal is to offer innovative perspectives for the future development and formulation of antibacterial agents targeting FabH.

In this study, indeno[1,2-b]indolone scaffolds were assembled through an operationally simple, aqueous Cu(OAc)₂ catalyzed three-component domino reaction furnishing mono-, bis- and tris-analogues in 68–95% isolated yields under mild conditions (60–85 °C, ≤ 150 min). Antimicrobial profiling (MIC & IC₅₀, 125 µg disc) against six clinically relevant strains revealed a steep electronic gradient: electron-withdrawing (EW) substituents usually drive sub-μg mL⁻¹ potency, whereas electron-donating (ED) groups abolish activity (>100 μg mL⁻¹). The meta-chloro mono-derivative 19g reaches 0.06 μg mL⁻¹ against (Bacillus subtilis) B. subtilis and (Escherichia coli) E. coli (equipotent to gentamicin, 2-fold above ampicillin), while the tris-expanded 23 breaches 0.015 μg mL⁻¹ 9-fold superior to ampicillin and the first indeno-indolone to match reference antibiotics without surpassing them. Mechanistic cues (ROS burst & DNA-gyrase docking) support a dual-mode action: membrane disruption plus topoisomerase inhibition. The scalable, metal-light protocol and clear EW > push–pull > ED ranking offer immediate lead-optimization handles to close the remaining 4–8-fold fungal gap versus Amphotericin B and to attenuate Gram-negative efflux, positioning 23 as a credible next-generation antibiotic candidate.

(‒)-Xanthorrhizol (1), a natural sesquiterpenoid isolated from Curcuma aromatica rhizomes, exhibits notable anti-inflammatory activity by inhibiting nitric oxide (NO) production. To enhance its NO inhibitory activity, a series of 22 analogs were synthesized through chemical modifications, including alkylation, esterification, hydrogenation, oxidation, and oximination. The NO inhibitory activities of these analogs were evaluated in LPS-stimulated RAW264.7 macrophage cells using the Griess method, while cytotoxicity was assessed with the MTT assay. Among the tested compounds, the oxime analog 23 demonstrated the strongest NO inhibitory activity (IC₅₀ = 9.4 µM, SI = 13.2), significantly outperforming the reference drug aminoguanidine (IC₅₀ = 29.5 µM, SI > 5.4). Structure–activity relationship (SAR) analysis revealed that electron-donating substituents and increased molecular rigidity generally decreased NO inhibition potency. However, some modifications also increased cytotoxicity against RAW264.7 cells. In addition, the oximation of xanthorrhizol enhanced NO inhibitory activity approximately 5-fold compared with the parent compound, while maintaining similarly low toxicity. These SAR findings underscore the critical influence of the oxime substructure in modulating NO inhibitory activity. Notably, the oxime analog 23 emerges as a promising lead candidate for the development of anti-inflammatory agents targeting NO-mediated pathways.

Beilschmiedia (the family Lauraceae) is a large tropical genus containing species traditionally used to treat rheumatism, tumors, malaria, infections, and others. Despite extensive ethnomedicinal applications, a comprehensive evaluation of its phytochemistry and pharmacology remains limited. This review aims to consolidate current knowledge on the phytochemical diversity, biosynthetic and synthetic pathways, pharmacological potential, and chemical modifications of Beilschmiedia species. Relevant studies were retrieved from PubMed, Scopus, Web of Science, and Google Scholar up to September 2025 using “Beilschmiedia” as the main keyword. Eligible publications included original reports on phytochemical isolation, structure elucidation, biosynthetic studies, synthetic modification, and pharmacological evaluation, whereas botanical identifications were excluded. Over 240 compounds were characterized from 30 Beilschmiedia species, encompassing tetracyclic polyketides, alkaloids, terpenoids, phytosterols, lignans, neolignans, flavonoids, alkamides, and others. Endiandric acids and cyclobutane/oxetane-type neolignans, possessing unique skeletons, could be chemotaxonomic significance. Pharmacological studies have revealed diverse activities, such as cytotoxic, antimicrobial, antimalarial, antioxidant, anti-inflammatory, antidiabetic, and cholinesterase-inhibitory activities. Advances in biosynthesis, total synthesis, and semi-synthetic modification have facilitated the exploration of structure-activity relationships. Beilschmiedia represents a valuable reservoir of chemically novel and biologically active compounds. Future research should expand phytochemical surveys to underexplored species, integrate metabolomic and genomic approaches, and conduct advanced pharmacological studies, including in vivo validation and formulation development.

Medicinal plants are an invaluable source of specialized metabolites with unique and complex chemical structures. This chemical diversity offers a rich resource for discovering new compounds with therapeutic potential. One notable example is Ageratina petiolaris, which produces a mixture of esters of 2α-hydroxyeperuic acid (1) in high quantity. The ent-labdane 2, a product of the alkaline hydrolysis of 1, possesses a chemical structure with promising therapeutic potential. In this work, aniline, cyclohexylamine, 4-chloroaniline, bencilamine, p-cinnamyl alcohol, phenol, 4-bromophenol, and 4-methoxyphenol were used to prepare ester and amide derivatives of 2 in a one-pot process aided with sonochemistry, yielding the respective compounds in moderate to good yields. Additionally, the antiproliferative potential of the amides and esters was tested in vitro against MCF-7, HeLa, A549, and K562 cancer cell lines. The results showed significant cytotoxic activity for almost all the evaluated derivatives, making them promising candidates for potential therapeutic agents against certain types of cancer.