Chemical Biology & Drug Design最新文献

Fifteen new hydrazine derivatives were synthesized and structurally characterized using NMR (¹H NMR and ¹³C NMR) spectroscopy techniques. Furthermore, the crystal structure of compound 1647 was figured out by the single crystal X-ray analysis. The in vitro antimicrobial activity was reviewed against five species of pathogenic bacteria (Escherichia coli [ATCC 25922], Serratia marcescens, Klebsiella pneumoniae [ATCC 13883], Staphylococcus aureus [ATCC 29213], Enterococcus faecalis [ATCC 2942]) and three fungal species (Candida albicans [ATCC 24433], Candida krusei [ATCC 6258], and Candida parapsilopsis [ATCC 22019]). Compounds 1646 and 1647 with MIC of 1.95 μg/mL was found to be most active against E. coli (ATCC 25922). The presence of bromine or tert-butyl groups in the para position of the phenyl ring increased the antibacterial activity. It has been shown by SEM study that these compounds cause deterioration in the morphology of E. coli. Using DFT, the X-ray geometry and model geometry of compound 1647 were optimized and compared in terms of both energy and geometry, and it was determined that they were conformers of each other with a difference of 0.11 kcal/mol.

Cancer is among the leading causes of death in the world today. Several strategies were used to control cancer including chemotherapy, radiotherapy and targeted therapy. Among the problems related to antiproliferative chemotherapy against cancer is the medication resistance which require continuous generation of new agents. These new potential agents could be extracted from natural sources or prepared synthetically. This research represents the preparation of new heterocycles incorporating an indenopyridazine nucleus as potential antiproliferative agents. The synthetic strategy was initiated by the treatment of ninhydrin with cyanoacetohydrazide resulting in the formation of the key intermediate indeno[2,1-c]pyridazine scaffold 4, which undergoes condensation with various nitrogenous nucleophilic reagents (namely: phenyl hydrazine, substituted benzohydrazide, and thiosemicarbazide). Cyclization of thiosemicarbazone derivative 8 with ethyl bromoacetate furnished the target compound thiazolin-4-one derivative 9, which was condensed with three 5-aryl-1H-pyrazole-4-carbaldehydes to furnish the corresponding 5-arylidene-thiazolin-4-one derivatives 11a-c. In addition, thiosemicarbazone derivative 8 undergoes reactions with α-chloroesters 12 or α-chloroketones 14 to yield the indenopyridazine-thiazole hybrids 13 and 15, respectively. The cytotoxic activity of the targeted indeno[2,1-c]pyridazine compounds was explored against four cancer cell lines in vitro. Indenopyridazine-thiazolin-4-one hybrid 11c exhibited the highest cytotoxicity against HepG2 (IC₅₀ = 7.43 μM) and MCF-7 cells (IC₅₀ = 4.37 μM). Their IC₅₀ values were very close to the reference drug 5-fluorouracil. Also, compound 7b was found to show a very strong cytotoxic effect against HepG2 (IC₅₀ = 10.20 μM) and MCF-7 (IC₅₀ = 7.39 μM). Moreover, molecular docking indicated that compounds 11b, 7b, and 11c had the best docking score against vascular endothelial growth factor recetor-2 (VEGFR-2) which is the potential target predicted by target fishing.

The use of transformer models in drug design is gradually emerging. The models are applied in chemical structure prediction and target discovery. Textual sequences and graphs are commonly used to describe molecules. In this review, we discussed the application of transformers and their advantages in different prediction tasks. We further elaborated on their applications in various aspects of drug discovery, including the SMILES principle, spectrum prediction, drug response prediction, chemical structure prediction, drug–drug interaction and activity prediction, drug target interaction, and protein prediction. We compared the differences between transformer and traditional drug discovery and then presented our proposed resolutions to this challenge. In the future, advancements will lead to the development of more efficient models with superior parameters. Transformer models can incorporate any input. Combining the transformer with different models and algorithms can also enhance the operational performance for multimodal and multitask prediction.

Praeruptorin A (PA), a monomer derived from the traditional Chinese medicine Peucedani Radix, is known for its therapeutic properties, including heat clearance, phlegm dissolution, and asthma relief. Sepsis, characterized as a systemic inflammatory response syndrome (SIRS), is triggered by a cytokine storm resulting from pathogenic infection and can progress to multi-organ failure. This study investigates and predicts the effective molecular targets and potential mechanisms of PA in the context of sepsis through the application of network pharmacology. The identified targets were subsequently validated using an in vitro molecular model, thereby providing a robust theoretical basis for our findings. Our results indicate that PA significantly reduced malondialdehyde (MDA) accumulation, ameliorated glutathione (GSH) depletion, enhanced glutathione peroxidase 4 (GPX4) expression, and restored mitochondrial function. Notably, PA markedly decreased prostaglandin-endoperoxide synthase 2 (PTGS2) expression, which collectively suggests that PA may inhibit ferroptosis. We propose that PA may exert its inhibitory effects on ferroptosis in macrophages via modulation of PTGS2, highlighting its potential as a drug for sepsis treatment.

The clinical challenges of treatment resistance and adverse reactions associated with targeted drug toxicity require significant expenditure on the development and trials of new therapeutic molecules. Such an approach as molecular repurposing allows “giving a second life” to available drugs by targeting them to new biotargets and testing them in various combinations. When developing new therapeutic strategies, it is important to consider the unique characteristics of different cancer tissues. Tumors of different organs may have different molecular profiles, and effective treatment should be directed exactly at targets specific to these tissues. This literature review is devoted to analyzing the current state of the pharmacological niche of protein kinase inhibitors, synthesis methods and the mechanism of action of existing approved drugs—inhibitors of major protein kinases. In addition, in this review we highlight modern approaches to modeling 3D tissue-specific organoids (tumoroids) used for testing anticancer agents, which are currently considered a promising platform for screening protein kinase inhibitors. Molecular drug repurposing and the next generation 3D organoids are important strategies in the fight against resistance to targeted drugs and in the development of new, more effective therapeutic agents.

Madecassoside (MC) is an anti-inflammatory and antibacterial active substance extracted from the traditional Chinese medicine Centella asiatica. Based on network pharmacology and experimental validation, this study assessed MC's anti-breast cancer (BC) actions and related molecular pathways. CCK-8, Trypan Blue, and Hoechst33342/PI assays showed that MC significantly reduced BC cell activity, but it had little inhibitory effects on normal cells. Network pharmacology analysis predicted 40 intersection targets between MC and BC, 291 GO-related biological processes, and 105 KEGG signaling pathways. The anti-breast cancer activity of MC is closely related to reactive oxygen species (ROS), AKT and MAPK signaling pathways. Through Annexin V-FITC/PI, flow cytometry, transwell, wound healing and western blotting experiments, it was found that MC induced mitochondria-dependent apoptosis, G2/M phase arrest and inhibited cell migration of MDA-MB-231 cells through MAPK/STAT3/NF-κB signaling pathway, PI3K/AKT signaling pathway and AKT/GSK-3β/β-catenin signaling pathway, respectively. The induction and blocking effects were inhibited by the addition of ROS scavenger N-acetyl cysteine (NAC). Molecular docking showed that MC had significant binding ability with STAT3, CASP3, BCL2 and JUN targets in BC. In summary, MC induced apoptosis, cell cycle arrest, and migration inhibition via ROS-mediated MAPK/STAT3/NF-κB, PI3K/AKT, and AKT/GSK-3β/β-catenin signaling pathways in MDA-MB-231 cells.

Glutathione reductase (GR) plays a pivotal role in cellular metabolism by maintaining redox balance and sulfhydryl homeostasis through the regeneration of reduced glutathione (GSH). In tumor cells, GR is overexpressed, supporting enhanced antioxidant defenses and neutralizing the detrimental effects of reactive oxygen species. In this study, a series of sulfonyl hydrazone analogs bearing phenolic Mannich base moieties were synthesized and characterized as potential GR inhibitors. The compounds exhibited inhibitory activity with IC₅₀ values ranging from 198.1 to 3013 nM. In silico analyses revealed that 6a binds to the NADP⁺ binding site of the hGR enzyme and interacts with key residues involved in electron transfer, leading to reduced enzyme activity. Compound 6a, the most potent hGR enzyme inhibitor identified in this study, exhibited cytotoxic effects against MCF-7, A549, and HeLa cancer cell lines with EC₅₀ values of ~1.52, ~17.5, and ~8.82 mM, respectively. Notably, compound 6a demonstrated only weak cytotoxicity at the millimolar level, particularly against the MCF-7 cell line. Given its strong inhibitory activity toward the hGR enzyme, enhancing the membrane permeability of compound 6a may improve its cellular uptake and potency, thereby supporting its potential as a promising anticancer drug candidate.

Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.