Medicinal Chemistry Research最新文献

An acetophenone thiosemicarbazone series 6a-m containing lactose moiety were synthesized and explored for their inhibition against the enzymes responsible in Type 2 diabetes mellitus (T2DM), including α-amylase, α-glucosidase, DPP-4, and PTP1B. Two thiosemicarbazones exhibited the highest inhibitory activity against these enzymes, 6i against α-glucosidase (IC₅₀ = 7.15 ± 0.12 μM) and 6m against α-amylase, DPP-4, and PTP1B (with IC₅₀ = 7.82 ± 0.14 µM, 1.32 ± 0.02 µM, and 3.74 ± 0.14 μM when compared to the corresponding standard drugs). These compounds also exhibited the high anti-glycation and antioxidant activity in DPPH and ABTS^•+ scavenging assays. They were noncytotoxic for WI-38 cell line with IC₅₀ >85 μM. Molecular docking study applied to these two most potential inhibitors on enzymes, including 3TOP for inhibitor 6i, 1OSE, 3W2T, and 1NNY for inhibitor 6m. These ligands had active interactions with the residues in the catalytic pocket of these corresponding enzymes that was consistent with their obtained inhibitory efficacy against each enzyme tested. The 300 ns molecular dynamics simulations applied for the complexes, including 6m/1OSE, 6i/3TOP, 6m/3W2T, and 6m/1NNY, to validate the obtained in vitro biological activity data of these inhibitors. The obtained results indicated that these inhibitors had stable dynamic interactions in the catalytic pockets of the respective enzymes to promote their activity.

This study focused on synthesizing novel chalcone-ketamine derivatives and evaluation of their anti-inflammatory properties. Eighteen compounds were synthesized via a one-pot condensation of ketamine with various aldehydes under basic conditions. Compounds were characterized by FTIR, NMR, mass spectrometry, and elemental analysis. Molecular docking studies revealed that several of these molecules possessed low binding affinities for COX-2 than COX-1. An in vitro enzyme inhibition analysis of molecules also suggested similar trend with compounds 1n and 1q exhibiting the greatest preferential inhibition of COX-2 than COX-1. Key structural modifications such as specific functional groups in compounds 1n and 1q were identified through SAR analysis. QSAR modeling revealed a predictive correlation between structural features and inhibitory potential of synthetized molecules. Molecular dynamics (MD) simulations of the best-docked complex were carried out to assess the stability and dynamics of compound-receptor complexes followed by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations. Density functional theory studies were also performed on molecules 1n, 1q and ketamine to determine the energy of frontier molecular orbitals, HOMO-LUMO band gap and Mulliken charges on the optimized structures. Significant steric and electrostatic descriptors were found to influence COX-2 selectivity. In vivo analgesic and anti-inflammatory effects of 1n and 1q were further evaluated in hotplate, acetic acid-induced writhing, and carrageenan-induced paw edema models, with both compounds showing significant anti-inflammatory activities. Biochemical analysis indicated significant reductions in inflammatory mediators (IL-1β, TNF-α, COX-2) in the paws of mice treated with 1n and 1q than disease controls. In conclusion, novel chalcone-ketamine derivatives were synthesized with preferential inhibitory activity for COX-2 than COX-1.

Excoecaria cochinchinensis Lour. is a well-known medicinal plant in Vietnam, whose parts, particularly leaves, are applied as essential medicine in folk remedies. In this study, the chemical constituents of the plant’s aerial parts, together with their feasibility in enzyme inhibition and antioxidants, were investigated. Seven compounds, including a new coumarino lignan – excochinlignan (1), five known flavonol derivatives (2-6) and one monophenolic (7), were isolated and identified via chromatographic and spectroscopic approaches. In vitro biological evaluation of these compounds revealed the potential of kaempferol (2) and its glycosides (3-6) in all assays. Among them, kaempferol (2) was determined as the most active antioxidant (IC₅₀ 2.86 μM) while its 3-O-xylose derivatives (3) displayed the most significant α-glucosidase (IC₅₀ 65.88 μM) and tyrosinase (IC₅₀ 58.97 μM) inhibition. In silico evaluation via molecular docking simulation suggested the supportive effect of 3-O-xylose, C-4′ hydroxyl and C-4 ketone moieties in the structure of the isolated flavanols (2-6) on their enzyme inhibition and antioxidant properties.

Human toxocariasis is a globally neglected parasitic disease, commonly treated with benzimidazole anthelmintics. However, their efficacy is considered unsatisfactory, requiring the research and development of new drugs. Studies have shown that hetero-cyclic compounds with nitrogenous molecules are known for their properties of inducing oxidative stress on pathogens. This study aimed to evaluate the efficacy of the (E)-N’-benzylidenefuran-2-carbohydrazide (PFUR) and ten derivatives against Toxocara canis in preclinical tests. The compounds were tested in vitro, in duplicate, at a concentration of 1.0 mg/mL to 0.062 mg/mL in a microplate containing 100 Toxocara canis larvae in RPMI-1640 medium. The compound PFUR 2 showed activity against 100% of the larvae at the minimum larvicidal concentration (MLC) of 0.25 mg/mL and was selected for the subsequent tests. Furthermore, this compound also demonstrated non-cytotoxicity to murine macrophages and an adequate estimate of oral bioavailability, as determined by the “rule of five” in computational models. After, two in vivo tests were conducted on Swiss mice. In the groups treated with PFUR 2 (10 mg/kg/5 d, IG), 10 days and 30 days after inoculation with 500 T. canis eggs, there was a reduction of 23% (p > 0.05) and 62.4% (p < 0.05) in the intensity of infection, respectively, compared to the PBS control. In both experiments, the PFUR 2 compound presented results similar to those of mebendazole (40 mg/kg/5 d, IG) (p > 0.05). The results of this study demonstrated the potential of this compound as a candidate for a new anthelmintic.

The escalating challenge of antimicrobial resistance (AMR) necessitates the development of novel therapeutic agents. In this study, we present an efficient, eco-friendly, and metal-free multicomponent synthesis of a new series of pyrazole-fused 2-amino-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives (7a–j) via a piperidine-catalyzed, solvent-free liquid-assisted grinding (LAG) method. This green synthetic approach yields the target compounds in excellent yields without the need for purification or toxic reagents. The synthesized compounds were evaluated in vitro for antimicrobial activity against gram-positive (Bacillus cereus, Staphylococcus aureus), gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, and pathogenic fungi (Candida albicans, Candida tropicalis). Notably, derivatives 7b, d, e, and j exhibited significant activity, with minimum inhibitory concentration (MIC) values comparable to or exceeding those of standard drugs. Structure–activity relationship (SAR) analysis and in silico ADME profiling of the active compounds (7b, d, e and j) revealed favorable pharmacokinetic and safety profiles, highlighting their potential as promising antimicrobial candidates. This work underscores the value of green synthetic methodologies in drug discovery and provides a foundation for the further development of pyrano[3,2-h] quinoline-based antimicrobial agents.

Graphical Abstract

Hydroxypyranone ligands, in particular maltol and kojic acid, have proven to be promising building blocks in the development of transition metal-based anticancer agents. Their ability to chelate biologically relevant metal ions such as vanadium, copper, zinc and ruthenium enables the formation of stable coordination complexes with significant cytotoxic and pro-apoptotic activity. This review highlights the structural characteristics of hydroxypyranone ligands and their influence on the pharmacological properties of metal complexes. Notable systems, including bis(maltolato)oxovanadium(IV) (BMOV), VO–phen complex(Metvan) and Ru(II)–maltol complexes, have shown higher selectivity and lower systemic toxicity compared to classical chemotherapeutic agents such as cisplatin. The most important mechanisms of action include interaction with DNA, the formation of reactive oxygen species (ROS), mitochondrial dysfunction and the inhibition of enzymes. This review highlights the antitumor activity of copper(II), vanadium(IV/V), and ruthenium(II) complexes against hepatocellular and colorectal cancer cell lines. The review highlights the importance of rational ligand design, redox activity and metal ion selection for optimizing the therapeutic index of metallopharmaceuticals. Future perspectives point to the integration of these compounds into advanced drug delivery platforms and their evaluation in preclinical and clinical settings. This review emphasises the therapeutic importance of hydroxypyranone–metal complexes as selective and less toxic alternatives to platinum drugs. It provides new insights into their structure–activity relationships and supports their development as promising candidates for targeted cancer therapy.

Ivermectin is the most extensively researched macrocyclic lactone due to its potential anticancer and antiparasitic use. Nonetheless, there are more compounds within this family, including doramectin and abamectin. In the current era of medicinal repurposing, ivermectin has received renewed focus following its initial development for the treatment of parasitic conditions such as scabies, elephantiasis, and river blindness. Recent studies indicate that ivermectin may inhibit the proliferation of specific tumor cells by regulating many signaling pathways implicated in cancer progression. Despite the growing body of research on the topic, critical issues about its anticancer processes remain unresolved. Our study focused on ivermectin, its mechanisms of action, and its potential uses against glioblastoma multiforme (GBM).

The epidermal growth factor receptor (EGFR) is overexpressed in various cancers and contributes to tumor progression and therapeutic resistance. Although EGFR-targeting small-molecule inhibitors are clinically available, their limited efficacy and acquired resistance pose major challenges. In this study, we designed and synthesized a novel class of dual proteolysis-targeting chimeras (PROTACs) incorporating the natural product derivative Potassium Dehydroandrographolide Succinate (PDS) as the protein of interest (POI) ligand. PDS was selected as the POI ligand due to its structural similarity to andrographolide, a natural compound known to inhibit EGFR signaling, suggesting that PDS may retain EGFR-binding potential despite lacking direct anti-tumor reports. Unlike conventional PROTACs, these molecules feature two CRBN E3 ligase ligands symmetrically attached via distinct linkers, thereby enhancing the likelihood of ternary complex formation and promoting more efficient EGFR degradation. Among the synthesized compounds, DP6 exhibited the most potent anti-proliferative activity in MCF-7 cells, with a 3.8-fold improvement over the parent PDS molecule. Western blotting confirmed that DP6 induced concentration-dependent EGFR degradation via the ubiquitin–proteasome system, suppressed downstream JAK2-STAT3 signaling, and promoted apoptosis. This study not only demonstrates the feasibility of utilizing structurally modified natural products as POI ligands, but also introduces a unique dual-ligand PROTAC architecture that may provide enhanced degradation potency for traditionally “undruggable” targets.

We report the design and synthesis of PROTACs based on (3 R,4 R)-4-((5-chloro-4-(4-fluoro-2-(2-hydroxypropan-2-yl)-1-isopropyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)piperidin-3-ol, using diverse linkers and pomalidomide as a CRBN ligand. Molecular modeling experiments were conducted to arrive at the optimal exit vectors on both the warhead and pomalidomide to enable efficient linker attachment. Most of the PROTACs exhibited good binding affinity (IC₅₀ between 0.04 µM to 1.50 µM) with CDK4/6 and the binary complex formation data correlated with the ternary complex formation. Selected PROTACs (compounds 4, 7, and 13) were tested in Jurkat cells at varying concentrations to assess CDK4/6 protein degradation. Compound 7 showed a DC₅₀ of 2.0 and 4.0 nM against CDK4 and CDK6 respectively, whereas compound 13 showed a DC₅₀ of 6.0 nM against both CDK4 and CDK6. These results highlight PROTACs 7 and 13 as promising leads for further therapeutic development.

Photodynamic therapy (PDT) is a promising treatment for diseases like cancer and microbial infections, relying on light-activated photosensitizers to generate cytotoxic reactive oxygen species. While PDT has shown clinical success, developing novel photosensitizers with improved properties remains challenging. Ferrocene, with its unique stability, redox activity, and tunability, offers an attractive scaffold for this purpose. This review delves into the recent advancements in ferrocene-based photosensitizers, exploring their design strategies, mechanisms of action, and diverse applications in medicinal chemistry. We critically discuss their potential, comparing structure-activity relationships across various ferrocene derivatives and evaluating their performance in in vitro cell line assays. Additionally, we address current challenges and future directions, highlighting their potential to significantly advance PDT and offer new therapeutic avenues.