Molecular Diversity最新文献

A series of novel dual-action statin conjugates, which exhibit both triglyceride and cholesterol lowering activities, have been systematically designed, synthesized, and subjected to comprehensive pharmacological evaluation. All the target compounds were characterized by ¹HNMR, ¹³CNMR, and HRMS. Biological evaluation demonstrated that the majority of the synthesized compounds exhibited significant lipid-lowering and cholesterol-reducing activities. In particular, ligand 8a demonstrated significant potency, resulting in a marked reduction in cholesterol and triglyceride levels in a dose-dependent manner. Its minimum response has lowered 2.778 mmol/L (cholesterol level) and 0.699 mmol/L (triglycerides level), surpassing the positive control. For the preliminary assessment of the safety of the target compound, the ADMETlab 2.0 predictive software was utilized. Data show that compared to the combination of drugs used clinically, the safety of the target compounds may be improved. These findings suggest that compound 8a holds promise as a potential candidate for the treatment of hyperlipidemia.

Sparganii Rhizoma (SR) has demonstrated promising anticancer effects across various malignancies; however, its mechanisms in laryngeal cancer (LC) remain poorly understood. This study employs network pharmacology and molecular docking to investigate the molecular mechanisms underlying SR's therapeutic effects on LC, providing novel insights for its potential use in treatment. Active compounds and targets of SR were identified through the TCMSP and Pharmmapper databases, while LC-related targets were sourced from GEO, GeneCards, OMIM, and PharmGkb databases. A Venn diagram generated from these datasets highlighted 58 overlapping targets. The STRING database and Cytoscape 3.9.1 software facilitated the construction of a protein-protein interaction network for these targets, and R language analysis revealed 15 core targets. GO and KEGG enrichment analyses, conducted with the ''clusterProfiler'' package, identified relevant biological processes, cellular components, and molecular functions associated with LC treatment. KEGG analysis suggested SR primarily regulates pathways such as TNF, IL-17, and P53. Molecular docking confirmed SR's ability to bind effectively to the 15 core targets. Molecular dynamics simulations further validated stable protein-ligand interactions for MAPK1, GSK3B, and MAPK14. Core target validation across transcriptional, translational, and immune infiltration levels was performed using GEPIA, HPA, cBioPortal, and TIMER databases. In conclusion, network pharmacology, molecular docking, and dynamics simulations provided insights into SR's mechanism in LC treatment, forming a theoretical basis for further investigation of its therapeutic potential.

Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC₅₀ values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF^V600E. Compound 4e exhibited the highest inhibitory activities, with IC₅₀ values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF^V600E, compared to the reference drugs erlotinib (IC₅₀ 0.06 ± 0.002 μM) and vemurafenib (IC₅₀ 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF^V600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF^V600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.

Neuraminidase (NA) is an essential enzyme located at the outer layer of the influenza virus and plays a key role in the release of virions from infected cells. The rising incidence of global epidemics has made the urgent need for effective antiviral medications an urgent public health priority. Furthermore, the emergence of resistance caused by specific mutations in the influenza viral genome exacerbates the challenges of antiviral therapy. In view of this, this study aims to identify and analyse possible inhibitors of NA from different subtypes of influenza viruses. Initially, a thorough search was conducted in the Protein Data Bank (PDB) to gather structures of NA proteins that were attached with oseltamivir, a widely recognized inhibitor of NA. Here, 36 PDB entries were found with NA-oseltamivir complexes which were studied to evaluate the diversity and mutations present in various subtypes. Finally, N1(H1N1) protein was selected that demonstrated low IC50 value of oseltamivir with mutation H275Y. In addition, the study utilized BiMODAL generative model to generate 1000 novel molecules with comparable structures to oseltamivir. A QSAR model, based on machine learning (ML), was built utilizing the ChEMBL database to improve the selection process of candidate inhibitors. These inhibitors were subsequently analysed by molecular docking and further the best hits compounds (compound_375, compound_106 and compound_597) were appended to make a bigger molecule (compound_106-375, compound_106-597, and compound_375-597) to fit into the binding pocket of protein. Further, triplicate molecular dynamics simulations lasting 100 ns to assess their effectiveness and binding stability showed that compound_106-375 had the most stable binding with the protein. Key residues, including Asn146, Ala138, and Tyr155, form critical interactions with the ligand, contributing to its stability. The investigation was enhanced by employing principal component analysis (PCA), free energy landscape (FEL), and binding free energy calculations. The total binding free energy (G_TOTAL) of - 169.62 kcal/mol suggests that the contact between compound_106-375 and the mutant N1 (H1N1) protein is thermodynamically favourable. This approach allowed for a thorough comprehension of the binding interactions and possible effectiveness of the discovered inhibitors. Overall, these findings demonstrate that compound_106-375 exhibits favourable binding characteristics and stability. Further experimental validation is required to confirm its efficacy against the H275Y mutant neuraminidase protein and its potential to overcome influenza drug resistance. However, compound_106-375 is suggested as a promising candidate for further development as a therapeutic agent against the mutant N1 (H1N1) protein. This finding will assist in drug development and to overcome the challenges associated with drug resistance in influenza strains.

To further explore and discover natural products-based antifungal agents, seventeen tertiary amide-oleanolic acid hybrids were designed and synthesized, and structurally confirmed by ¹H NMR, ¹³C NMR, HRMS, and melting point. Bioassay results illustrated that derivative 4 k exhibited prominent in vitro inhibitory activity against the mycelium growth of Gaeumannomyces graminis and Valsa mali with the EC₅₀ values of 41.77 and 43.96 μg/mL, respectively. Meanwhile, the structure-activity relationships were also summarized. Moreover, in vivo control efficacy demonstrated that derivative 4 k displayed remarkable curative effect (CE) against V. mali at 200 μg/mL with the value of 52.6%, evidently superior to that of the positive control carbendazim (41.5%). Besides, derivative 4 k also exhibited good CE against Botrytis cinerea at 200 μg/mL with the value of 33.0%. Scanning electron microscope analysis initially indicated that derivative 4 k may exert its antifungal effect by leading to abnormal morphology on the mycelium surface, resulting in the aberrant hypha growth.

This study addresses the urgent need for new drugs to combat multi-drug-resistant tuberculosis (MDR-TB). Focusing on MmpL3, a protein essential for mycobacterial cell wall synthesis, we designed and synthesised 50 new pyrazole-based amide derivatives. These compounds were then tested for their ability to inhibit the growth of various Mycobacterium tuberculosis (Mtb) strains, including both drug-susceptible and drug-resistant strains (resistant to isoniazid, rifampicin, or both). Two compounds, 15 and 35, emerged as potent inhibitors. They showed strong activity against both drug-susceptible and drug-resistant Mtb strains, with low minimum inhibitory concentration (MIC) values of 2 µg/mL and 2-4 µg/mL, respectively. Importantly, these compounds also demonstrated a high selectivity index, meaning they were significantly more toxic to Mtb cells than to human liver cells (HepG2). Compound 15 further proved to be bactericidal, effectively killing Mtb within six days. Interestingly, compounds 15 and 35 were inactive against lab-generated Mtb strains resistant to SQ109, a known MmpL3 inhibitor. This finding, supported by molecular docking, molecular dynamics simulations, and genetic analysis of the mmpl3 gene in the SQ109-resistant strains, strongly suggests that these novel compounds also target MmpL3. This research highlights the potential of pyrazole-based amides as a promising new class of anti-TB drugs. By targeting MmpL3, these compounds offer a novel mechanism of action to combat drug-resistant TB, potentially leading to improved treatment outcomes.

Azoheteroarenes-based photoswitches with high bidirectional isomerization and long thermal half-life (t_1/2) have attracted widespread attention from researchers. The diversity of molecular scaffolds has a profound impact on photoswitching performance, herein, we incorporated dynamic connection sites and scaffold optimization to construct a series of pyrazolyazoindole/indazoles (PAIs)-based photoswitches with adjustable photoswitching properties and versatile photophysical properties upon the irradiation of special wavelength, among them 4Z-H can be switched between states "lock" and "unlock" by Cu²⁺ ion and EDTA. Thermal stability of series 3Z and 4Z was more stable than other PAIs photoswitches for their intramolecular forces, while the steric effect weakened the thermal stability of series 5D, these results clarified the relationship between the PAIs scaffolds and their photoswitching properties. More importantly, ionic photoswitches (4D-N⁺) synthesized by modification of quaternary ammonium salt fragment exhibited excellent reversible photoswitching properties in aqueous solution with alkaline condition and concentrated glutathione (GSH). The assembly of fluorescence group (triphenylamine) endowed the PAIs scaffolds with optically controlled fluorescence properties. This research elucidated the relationship of scaffold-modification-function of PAIs and would inevitably provide a reliable foundation for the development of intelligent organic materials with photoswitching systems.

Multidrug resistance (MDR) presents a major challenge for effectiveness of chemotherapy. This study investigates the effectiveness of spiroindoline quinazolinediones in reversing MDR mediated by P-glycoprotein (P-gp) overexpression in cancer cells. A series of synthesized hybrid spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives (compounds 5a-5l) were analyzed for their ability to enhance rhodamine 123 (Rhd123) accumulation in the MES-SA/DX5 cell line using flow cytometry. The MTT assay was also employed to evaluate the compounds' effectiveness in reversing drug resistance. Additionally, docking studies and molecular dynamics simulations were conducted to investigate the interaction of these compounds with the P-gp transporter. The Rhd123 accumulation assay in MDR cancer cells revealed that most compounds, in particular 5f, 5g, 5h, 5i, 5j, 5k, and 5l, exhibited significant potential as P-gp inhibitors. Among the tested derivatives, compounds 5g and 5l demonstrated the best effects, and increased Rhd123 accumulation up to 12.9 times compared to untreated cells. Additionally, compounds 5f through 5 l bearing methylbenzyl (5f), benzyl (5g), pentyl (5 ), p-bromobenzyl (5i), p-chlorobenzyl (5j), dichlorobenzyl (5k), and tert-butylbenzyl (5l) substituents on the isatin ring effectively restored sensitivity to doxorubicin at their non-toxic concentrations in resistant MES-SA/DX5 cells. Among these, compound 5l at 5 μM exhibited the highest inhibitory potential, and lowered doxorubicin's IC₅₀ value 10.1 times compared to control. Moreover, in silico investigation identified the potential interactions of test compounds with critical residues of P-gp involved in its efflux function. Our study suggests that the synthesized spiroindoline quinazolinediones may have high potentials as agents capable of reversing MDR in cancer cells.

Helicobacter pylori (H. pylori, Hp) is a primary contributor to various stomach diseases, including gastritis and gastric cancer. This bacterium can colonize gastric epithelial cells, compromising their integrity and leading to the development of these conditions. While antibiotics are the mainstay of treatment for H. pylori infections, their widespread use has led to serious issues with drug resistance. High-temperature requirement A (HtrA) protein is an active serine protease secreted by H. pylori, which can destroy gastric epithelium, thus helping H. pylori to colonize gastric mucosa efficiently. In this study, we identified three compounds-Quercetin, Fisetin, and Geniposide-as potential natural compounds that might specifically interact with the HtrA protein, based on molecular docking and molecular dynamics simulations (MDs). The casein hydrolysis experiment indicated that Fisetin could inhibit the activity of HtrA in hydrolyzing casein at the concentration of 50 μM m. Additionally, our in vitro antibacterial experiments further showed that Fisetin could effectively inhibit the growth of H. pylori in a concentration-dependent manner, with an inhibition rate of 80% achieved at a concentration of 10 μM. In summary, these results suggest that Fisetin has an inhibitory effect on the growth of H. pylori, and this study may be the first to reveal its obviously inhibitory effect on HtrA protein. Our findings imply that Fisetin could be a potential candidate for further research as a therapeutic agent targeting protein HtrA, providing a new direction for the exploration of lead compounds and potential drugs against H. pylori infections.

Lung cancer is the world's top ranked cancer, with non-small cell lung cancer accounting for over 80% of lung cancer, so it is an urgent need to find new treatment strategies for non-small cell lung cancer. Celastrol is one of the effective active ingredients in the plant Tripterygium wilfordii Hook. f., and research has found that celastrol has an inhibitory effect on non-small cell lung cancer. However, the significant toxic side effect of celastrol limits its clinical application. In this study, 9 novel celastrol derivatives were developed using PROTAC technology. Cell viability testing displayed that some compounds exhibited higher antiproliferative activity in cancer cells, and had lower toxicity to normal cells. Among them, compound MX-108 (11c) showed a high inhibitory activity with an IC₅₀ value of 0.66 ± 0.07 μM against human non-small cell lung cancer NCI-H358 cells. The DIA-based quantitative proteomics and western blot analyses had confirmed that compound MX-108 could effectively degrade RAB9A protein in NCI-H358 cells. Compound MX-108 could downregulate the phosphorylation level of Akt and upregulate the expression of cleaved caspase 3. Molecular docking predicted that celastrol had a high binding ability with RAB9A protein. Furthermore, compound MX-108 could effectively inhibit tumor growth in xenografts model of NCI-H358 cells. This study provides new ideas for the development of novel celastrol derivatives to treat cancer.