Future medicinal chemistry最新文献

Aims: Despite advances in cancer therapy, tumor aggressiveness remains a challenge due to rapid progression and genetic variability. Tumor cells often overexpress glucose transporters (GLUTs) and receptors such as galectin and ASGP-R. Based on this, new chalcone derivatives conjugated to D-glucose, D-galactose, and lactose were synthesized from a previously identified cytotoxic chalcone (compound 1) to evaluate their anticancer potential.

Materials and methods: The compounds were synthesized as O-glycosides or glycosyl-1,2,3-triazole chalcones and tested against cancer and normal cell lines. Cellular assays assessed cytotoxicity, colony formation, migration, morphology, cell cycle progression, and apoptosis. Molecular docking and dynamics simulations investigated interactions with MMP-9, a key enzyme in metastasis.

Results: O-galactosyl chalcone 9 showed the most promising activity, surpassing compound 1 against HeLa (CC₅₀ 4.58 µM) and T-24 (CC₅₀ 4.41 µM) cells, with improved selectivity over doxorubicin. Chalcone 9 inhibited colony formation and migration, induced morphological changes, modulated the cell cycle, and triggered apoptosis in HepG2 and T-24 cells via p53-dependent and independent mechanisms. Molecular modeling has revealed stable interactions between the galactosyl moiety and MMP-9, supporting its role as a potential target.

Conclusions: Chalcone 9 exhibits potent, selective anticancer activity and anti-migratory effects, representing a promising candidate for further drug development.

Natural products (NPs) have long provided privileged scaffolds for drug discovery, yet their biosynthetic restrictions limit exploration of broader natural product chemical space. Pseudo-natural products (pseudo-NPs) have emerged as a promising strategy to overcome these limitations by recombining biosynthetically unrelated natural product fragments into unprecedented frameworks. These scaffolds retain NP-inspired features while extending into novel structural and functional space, often leading to bioactivities not achievable with classical derivatives. This review summarizes recent advances in pseudo-NP design, highlighting fragment selection, connectivity principles, cheminformatic evaluation, and the role of phenotypic profiling, particularly the cell painting assay (CPA), in functional annotation and mode-of-action elucidation. Representative scaffolds, including indotropanes, apoxidoles, pyrano-furo-pyridones, and pseudo-rutaecarpines, are discussed in the context of antiproliferative, anti-inflammatory, antibacterial, and autophagy-related activities. While only a few groups worldwide currently explore this field, the collective evidence underscores the translational promise of pseudo-NPs. Future progress will depend on broader scientific engagement, in vivo validation, and the expansion of fragment diversity to inspire the next generation of therapeutic agents.

Aims: Understanding protein-ligand binding site behavior is central to structure-based drug design. We analyzed amino acid composition and interactions in protein-ligand small-molecule binding sites and developed a novel method for binding site prediction.

Materials and methods: We analyzed the PDBBind+ database, which contains the largest protein-ligand binding site dataset known to us, using existing cheminformatics packages and in-house code. We used the resulting data to train a binding site prediction model.

Results: Within solvent-accessible binding regions, tryptophan, phenylalanine, tyrosine, methionine, and glycine, were enriched. Interaction analysis revealed hydrophobic contacts as the most frequent, followed by hydrogen bonds, water-bridged hydrogen bonds, salt bridges, π-π, π-cation, and occasional halogen interactions. We introduced the amino acid binding site enrichment index (ABSE), to support small-molecule binding site detection, and developed a model that discriminates binding site sequences from protein surface patches with 0.91 accuracy.

Conclusions: This work offers interpretable composition-interaction relationships and practical tool for binding site characterization. To facilitate application, we provide a free, open-source, fast, bindingsite identification tool (AABS), available at https://gitlab.com/Jukic/aabs. We anticipate that these findings and tool will advance binding site prediction and accelerate computationally intensive drug discovery within medicinal chemistry.

Cyclin-dependent kinases (CDKs) are central regulators of the cell cycle progression and transcription, making them attractive targets especially in oncology. The clinical success of CDK4/6 inhibitors in hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer has highlighted the therapeutic potential of CDK inhibition, along with ongoing clinical evaluation of other CDK-targeted agents. Despite the progress, challenges still remain due to off-target toxicity and the emergence of resistance. Recently, macrocycle-based drug design has gained recognition for its ability to enhance the kinase inhibitory activities and selectivity, improve drug-like properties, and potentially overcome resistance. This review summarizes recent advances (2015-2025) in macrocyclization strategies for CDK inhibitors, tracing the structural modification process from the acyclic scaffolds and highlighting their potential to address key limitations of current therapies.

Antimicrobial resistance remains a critical global health threat, driving the urgent need for novel therapeutic agents. Cannabinoids, bioactive secondary metabolites derived from Cannabis sativa, have gained attention for their promising antimicrobial properties. This review presents the latest advances in the antimicrobial properties of cannabinoids, emphasizing their activity against multidrug-resistant pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and selected Gram-negative bacteria. We summarize their antibacterial and antifungal effects, along with insights into structure-activity relationships that reveal the critical roles of functional groups such as the resorcinol moiety and alkyl side chain. Mechanistic studies suggest that membrane disruption, metabolic interference, and reactive oxygen species generation contribute to their antimicrobial action. Moreover, we summarize the synergistic potential of cannabinoids when used in combination with conventional antibiotics, highlighting both promising outcomes and notable limitations. Despite these advances, challenges such as poor solubility, limited in vivo data, and regulatory barriers persist. Addressing these gaps through focused medicinal chemistry and translational research will be essential to harness the full potential of cannabinoids as next-generation antimicrobial agents.

Background: The discovery of novel compounds as potential cancer drug candidates has garnered significant interest and widespread attention.

Aim: A novel series of benzimidazole-1,2,3-triazole-pyridine-glycosyl hybrids was rationally designed and synthesized to explore their potential anticancer activity.

Materials and methods: The targeted compounds were achieved via click chemistry. The acetylated N¹-glycosyl-1,2,3-triazoles were deprotected, producing the free hydroxy glycosides. Their cytotoxicity was evaluated against human colorectal (HCT-116), hepatic (HepG-2), and breast (MCF-7) cancers. Molecular docking and dynamics, in addition to Density functional theory (DFT) calculations, were studied.

Results & conclusion: Glycosyl-1,2,3-triazoles 15 and 17 exhibited the highest cytotoxic activity among the tested compounds, while others demonstrated selective efficacy against specific cancer cell lines. Notably, compound 17 showed a 1.808-fold increase in cytotoxicity compared to doxorubicin when tested on MCF-7 breast cancer cells (IC₅₀ = 33.32 µM). Molecular docking studies with the epidermal growth factor receptor (EGFR) indicated favorable-binding interactions and potential inhibitory effects. Molecular dynamics further confirmed the stable integration of 17 within the EGFR active site, preserving the structural integrity of its catalytic domain. DFT calculations provided insights into the electronic structure, molecular orbitals, and electrostatic potential of compound 17.

Aims: This study aimed to design and synthesize novel dehydroacetic acid (DHA) based pyrazole - pyridine conjugates and evaluate their potential efficacy in combating inflammation and malaria.

Materials and methods: A molecular hybridization strategy was employed to integrate the pyridine nucleus with two biologically active scaffolds, DHA and pyrazole. The target compounds were synthesized through a multi-step route involving the condensation of DHA with formyl-substituted pyrazoles to yield chalcone intermediates, followed by cyclization with malononitrile and ammonium acetate. The synthesized compounds were analyzed using spectroscopic techniques and tested in vitro for their anti-malarial and anti-inflammatory effects. Molecular docking studies were performed using PyRx 0.8 to predict binding interactions with key target enzymes - Enoyl-acyl-carrier-protein reductase (PDBID: 1NHG) and Cyclooxygenase-2 (PDB ID: 3LN1).

Results: Among the synthesized series, compound 5c exhibited the most potent activities, with an IC₅₀ of 0.96 ± 0.09 µM against Plasmodium falciparum and IC₅₀ of 7.23 ± 0.14 µM for significant anti-inflammatory activity. Docking results supported strong affinity toward both target enzymes.

Conclusions: The findings demonstrate that DHA based pyrazole - pyridine hybrids are promising dual-action scaffolds with significant anti-malarial and anti-inflammatory potential.

Purpose of objective: Novel heterocyclic analogs with dual antibacterial and anticancer potential were synthesized to address the limitations posed by multidrug resistance and current therapies.

Materials and methods: A series of N-heterocyclic peptoids was synthesized using the Ugi-multicomponent reaction. The obtained derivatives were evaluated for their antibacterial activity toward S. aureus and E. coli, as well as for their anticancer potential against A549 lung adenocarcinoma cells. Cytotoxic effects on Vero cells were also assessed. Furthermore, molecular docking and molecular dynamics simulations were performed to investigate the binding affinities and interaction stabilities of the compounds with target proteins.

Results: Compound 5d exhibited pronounced antibacterial activity against both bacterial strains. Furthermore, compounds 5k and 5l showed significant anticancer efficacy with minimal cytotoxic effects on normal cells. Molecular docking studies indicated strong binding affinities for compounds 5a, 5d and 5l, while molecular dynamics simulations confirmed the stability of the corresponding ligand-protein interactions.

Conclusions: The Ugi-derived peptoids exhibited potent antibacterial and anticancer activities, suggesting that their structural framework offers valuable insights for future structure-activity relationship studies and the design of novel therapeutic derivatives.

Aim: To design, synthesize, and evaluate a series of thiosemicarbazone and thiazolidin-4-one hybrids bearing arylsulfonate groups as potential androgen receptor-targeted anticancer agents.

Materials and methods: The compounds were synthesized via sequential sulfonylation, thiosemicarbazone formation, and cyclization to thiazolidin-4-ones. The structures of the compounds were characterized using NMR (¹H and ¹³C), FTIR, and HRMS spectroscopic techniques. In vitro cytotoxicity was assessed against prostate cancer (PC3) and human umbilical vein endothelial cell lines (HUVEC) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Molecular docking and MM-GBSA calculations were performed to predict binding affinities toward the androgen receptor. Molecular dynamics simulations (250 ns) were conducted to evaluate the stability and dynamics of the ligand - protein complexes.

Results: Thiazolidin-4-one derivatives, particularly compound 9, exhibited potent cytotoxicity (IC₅₀ = 6.35 µM) and high selectivity (SI = 6.05) over HUVEC cells. Docking and MM-GBSA analyses revealed strong interactions with key residues His-874, Met-742, Trp-741, and Arg-752. MD simulations confirmed minimal deviation from the docking pose (0.75 Å), low RMSD/RMSF values, and persistent hydrogen-bonding networks, supporting the structural stability and binding affinity observed in vitro. Structure-activity relationship (SAR) analysis indicated that scaffold cyclization and appropriate arylsulfonate substitution enhance receptor engagement and selectivity.

Conclusions: The combined synthetic, computational, and biological results demonstrate that thiazolidin-4-one-based hybrids, particularly compound 9, are promising selective androgen receptor-targeted anticancer agents, warranting further optimization and development.

Aims: To synthesize and characterize vanillin-mediated hydrazine derivatives (1a-j) and evaluate their in vitro antibacterial, antioxidant, and cytotoxic activities. This study is further supported by molecular docking, MD simulation, and DFT calculation studies.

Materials & methods: A series of one-pot multi-component Mannich-base vanillin-mediated hydrazine derivatives (1a-j) were synthesized and characterized by NMR, FTIR, and MS. The resulting compounds were subjected to in vitro studies, and the active compounds were further subjected to molecular docking using AutoDock Vina 1.1.2 and Discovery Studio. Molecular dynamics simulations via Desmond were performed to assess the docked complex stability, whereas DFT calculations were done using Gaussian 9.0.

Results: Compound 1j exhibited the highest activity against ESBLKP and ESBLEC compared to standard antibiotics in antibacterial activity, whereas 1c, 1d, and 1f demonstrated higher antioxidant activity relative to the standard. Highly active compounds 1j and 1f were further investigated for computational studies. Docking studies indicated favorable binding sites stabilized through hydrogen bonds and hydrophobic or halogen interactions at crucial residues.

Conclusions: In this study, compounds 1d, 1f, and 1j exhibited significant antimicrobial and antioxidant activities. These findings highlight the necessity for structural optimization to enhance their efficacy and specificity, and recommend further mechanistic studies.