Molecular Diversity最新文献

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.

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.

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.

Two new series of pyrimidinyl ethyl pyrazoles derivatives 13a-f and 14a-f were designed and synthesized to possess both anticancer effect by inhibiting BRAFV600E and anti-inflammatory effect by inhibiting JNK isoforms. The structure of the new compounds was generated from hybridization of two main moieties. The pyrimidinyl moiety from reported BRAFV600E inhibitors, and the pyrazole moiety from JNK isoforms inhibitors. The new final compounds were tested on BRAFV600E, JNK1, JNK2, and JNK3 to measure their kinases inhibitory effect. Compound 14c showed the highest activity on JNK isoforms and BRAFV600E with IC₅₀ = 0.51 μM, 0.53 μM, 1.02 μM, 0.009 μM on JNK1, JNK2, JNK3,and BRAFV600E, respectively. All final compounds were tested over four cancer cell lines related to the target enzymes. Compound 14d showed the most potent activity on all tested cell lines with IC₅₀ = 0.87 μM, 0.91, 0.42 μM and 0.63 μM on MOLT-4, K-562, SK-MEL-28, and A375 cell lines, respectively. The ability of 14d and 14c to inhibit MEK1/2 and ERK1/2 phosphorylation was performed by using western blot. The cell cycle analysis of compound 14d on A375 cell line revealed that compound 14d arrested cell growth at G0-G1 phase. Compound 14d remarkably decreased cell migration compared to control group in traditional migration test. Compounds 13a-f and 14a-f showed significant ability to inhibit nitric oxide release and PGE2 production on raw 264.7 macrophages. Compounds 13d and 14d exhibited high inhibitory effect on iNOS and COX-2 compared to COX-1. Finally, the effect of most potent compounds on TNF-alpha and IL-6 was determined.

α-Glucosidase inhibitors (AGIs) are pharmacological agents commonly used to manage postprandial hyperglycemia associated with type 2 diabetes mellitus (T2DM). Developing novel, potent AGIs remains a significant area of research. In this study, we investigated a series of derivatives of the natural product from α-mangostin as potential AGIs. A combined experimental and computational approach was employed to characterize promising compounds with potent α-glucosidase inhibitory activity. We found that α-mangostin (AM) and its derivatives (AM1 - 3) exhibited micromolar range α-glucosidase inhibition (IC₅₀ ranging from 15.14 to 67.81 µM), surpassing the known drug acarbose (IC₅₀ of 197.09 µM). Among the derivatives, AM1 exhibited the most promising α-glucosidase inhibition, displaying competitive inhibition kinetics with a K_i value of 47.04 µM. Molecular docking and molecular dynamics (MD) simulations provided mechanistic insights into the binding interactions between AM1 and the α-glucosidase active site. AM1 was observed to form hydrogen bonds and hydrophobic interactions with key amino acid residues within the enzyme's active site. The introduction of amine groups in compound AM1 enhanced activity compared to AM, the parent compound. This study highlights the potential of α-mangostin derivatives as potent AGIs. The identified lead compound, AM1, warrants further investigation to assess its efficacy and safety in managing T2DM.

Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in pathogen-mediated lung inflammation. Viral-induced cytokine release syndrome (CRS) has emerged as a global pandemic, characterized by a hyperactive immune response and excessive cytokine production causing irreversible lung injury. This study aimed to evaluate FDA-approved drugs for their potential to target hyperactive immune response and SARS-CoV-2 viral replication simultaneously. Six potential 3-CL^pro inhibitors were identified by molecular docking using MOE software, including ebastine (1), orlistat (2), atracurium besylate (3), piperaquine phosphate (4), valsartan (5), and acarbose (6), among which 1-3 binds strongly to the target protein with binding affinity of - 8.22, - 9.12, and - 7.81, kcal/mol, respectively. Additionally, all identified inhibitors except 4 revealed significant anti-viral potential, with a 50-100% reduction in SARS-CoV-2 plaques. Significant attenuation of phagocyte oxidative burst and inflammatory cytokines (IFN-γ, GM-CSF, IL-6, IL-2, IL-1β, TNF-α) demonstrated the immunomodulatory potential of these drugs. This study demonstrates the potential of pre-existing drugs to ameliorate the cytokine storm and oxidative damage with simultaneous anti-viral effects. The data provide pre-clinical support to develop these drugs as potential therapeutic agent against ARDS.

Telomerase, a reverse transcriptase implicated in replicative immortality of cancers, remains a challenging target for therapeutic intervention due to its structural complexity and the absence of clinically approved small-molecule inhibitors. In this study, we explored drug repurposing as a pragmatic approach to address this gap, leveraging FDA-approved drugs to accelerate the identification of potential telomerase inhibitors. Using a structure-based drug discovery framework, we screened the DrugBank database through a previously validated pharmacophore model for the FVYL pocket in the hTERT thumb domain, the established binding site of BIBR1532. This was followed by molecular docking, pharmacokinetic filtering, and molecular dynamics (MD) simulations to evaluate the stability of protein-ligand complexes. Binding free energy calculations (MM-PBSA and MM-GBSA) were employed for cross-validation, identifying five promising candidates. Experimental validation using the Telomerase Repeat Amplification Protocol (TRAP) assay confirmed the inhibitory potential of Raltitrexed, showing significant inhibition with IC₅₀ 8.899 µM in comparison to control. Decomposition analysis and Structure-Activity Relationship (SAR) studies further offered insights into the binding mechanism, reinforcing the utility of the FVYL pocket as a druggable site. Raltitrexed's dual mechanism of action, targeting both telomerase and thymidylate synthase, underscores its potential as a versatile anticancer agent, suitable for combination therapies or standalone treatment. As the top lead, Raltitrexed demonstrates the potential of repurposed drugs in telomerase-targeted therapies, offering a time and cost-effective strategy for advancing its clinical development. The study also provides a robust framework for future drug development, addressing challenges in targeting telomerase for anticancer therapy.

The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds IM-5 and IM-10 exhibited the best inhibitory activities with IC₅₀ value of 12.4 μM and 15.6 μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5 μM, respectively. ThT assay revealed compounds IM-5 and IM-10 exhibited the optimal Aβ_1-42 self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20 μM. In addition, compounds IM-5 and IM-10 exhibited low cytotoxicities and significant neuroprotective effects on Aβ_1-42-induced and H₂O₂-induced SH-SY5Y cell injury. More importantly, compounds IM-5 and IM-10 could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds IM-5 and IM-10 which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds IM-5 and IM-10 showed high hMAO-B inhibitory potency. In summary, all above results revealed compounds IM-5 and IM-10 might be promising multifunctional agents for AD treatment.