Molecular Diversity最新文献

With cabozantinib as the precursor, a novel small molecule inhibitors of c-Met kinase with thieno [2,3-b] pyridine as the scaffold were designed, synthesized and evaluated for their biological activity against A549, Hela and MCF-7 cell lines. The in vitro activities of 16 compounds were tested by MTT method with cabozantinib as control drug. Most compounds had moderate to strong inhibitory activities on cells. Among them, compound 10 had the strongest inhibitory activity, which was superior to the lead compound cabozantinib. Its IC₅₀ values for A549, Hela and MCF-7 cells were 0.005, 2.833 and 13.581 μM, respectively. The colony formation assay demonstrated that compound 10 significantly inhibited the colony formation of A549 cells and suppressed their growth in a concentration-dependent manner. The wound healing assay showed that compound 10 could effectively inhibit the migration of cancer cells compared to a blank control group. The AO/EB assay demonstrated that compound 10 possesses the capability to effectively trigger apoptosis in a concentration-dependent manner. The elementary structure-activity relationship, molecular docking and pharmacokinetics studies revealed the significance of thieno [2,3-b] pyridine derivatives in anti-tumor activity.

Gastric cancer poses a significant global health challenge, necessitating innovative approaches for biomarker discovery and therapeutic intervention. This study employs a multifaceted strategy integrating network biology, drug repurposing, and virtual screening to elucidate and expand the molecular landscape of gastric cancer. We identified and prioritized key genes implicated in gastric cancer by utilizing data from diverse databases and text-mining techniques. Network analysis underscored intricate gene interactions, emphasizing potential therapeutic targets such as CTNNB1, BCL2, TP53, etc, and highlighted ACTB among the top hub genes crucial in disease progression. Drug repurposing on 626 FDA-approved drugs for digestive system-related cancers revealed Norgestimate and Nimesulide as likely top candidates for gastric cancer, validated by molecular docking and dynamics simulations. Further, combinatorial synthesis of scaffold libraries derived from known chemotypes generated 56,160 virtual compounds, of which 76 new compounds were prioritized based on promising binding affinities and interactions at critical residues. Hotspot residue analysis identified GLU 214 and others as essential for ligand binding stability, enhancing compound efficacy and specificity. These findings support the therapeutic potential of targeting beta-actin protein in gastric cancer treatment, suggesting a future for further experimental validation and clinical translation. In conclusion, this study highlights the potential of repurposable drugs and virtual screening which can be used in combination with existing anti-gastric cancer drugs for gastric cancer therapy, emphasizing the role of computational methodologies in drug discovery.

Rheumatoid arthritis is a chronic autoimmune disease characterized by inflammation and joint damage, imposing a significant burden on affected individuals worldwide. Flavonoids, a class of natural compounds abundant in various plant-based foods, have shown promising anti-inflammatory and immunomodulatory effects, suggesting their potential as therapeutic agents for RA. In this study, we conducted a comprehensive investigation of identified LCMS compounds utilizing network pharmacology, computational modeling, in silico approaches, and pharmacokinetic assessment to evaluate the efficacy of flavonoids in RA treatment. The study identified 5 flavonoid structures with common targets via LCMS and Integration of network pharmacology approaches enabled a comprehensive evaluation of the pharmacological profile of flavonoids in the context of RA treatment, guiding the selection of promising candidates for further experimental validation and clinical development. The top 10 targets were AKT1, PI3KR1, CDK2, EGFR, CDK6, NOS2, FLT3, ALOX5, CCNB1, and PTPRS via PPI network. The investigation emphasized several pathways, including the AGE-RAGE signaling pathway, resistance to EGFR tyrosine kinase inhibitors, the PI3K-AKT signaling network, and the Rap 1 signaling pathway. In silico studies estimated binding affinities that ranged from - 7.0 to - 10.0 kcal/mol. Schaftoside and Vitexin showed no toxicity in computational approach and found suitable for further investigations. Overall, our study underscores the potential of flavonoids as therapeutic agents for RA and highlights the utility of integrative approaches combining network pharmacology, computational modeling, in silico methods, and pharmacokinetic assessment in drug discovery and development processes.

Plant-parasitic nematodes are seriously affecting agricultural production worldwide and there are few highly effective and low-risk nematicides to control nematode diseases. In order to discover new nematicides, a series of 1,2,4-oxadiazole derivatives containing amide fragments have been designed and synthesized with the principle of active substructure splicing. The nematicidal activity of the target compounds was evaluated in vitro and it indicated that compound C3 exhibited the most nematicidal activity against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus destructor with the LC₅₀ values of 37.2, 36.6, and 43.4 μg/mL, respectively, which were superior to positive agent tioxazafen. The preliminary mechanism results revealed that compound C3 not only inhibited the reproduction of B. xylophilus populations, but also affected the production of ROS and the accumulation of lipofuscin and lipids. Furthermore, compound C3 showed good inhibition of succinate dehydrogenase (SDH) with the IC₅₀ value of 45.5 µmol/L. Molecular docking indicated that compound C3 had excellent binding to amino acids around the SDH active pocket. This work indicated that 1,2,4-oxadiazole derivative containing amide fragment is a promising template for the discovery of new nematicides and compound C3 can be used as a potential nematicide candidate.

Acinetobacter baumannii is becoming a gravely threatening nosocomial infection with a higher mortality rate. The present study targets the BaeR protein that mediates resistance to tigecycline antibiotics. The BaeR protein, along with the aid of BaeS, senses the incoming antibiotics and stimulates the expression of resistance proteins. These resistance proteins efflux the antibiotics and protect the cells from its effect. The main goal of the current study is to determine potential inhibitors from already existing FDA-approved drugs that could mitigate the BaeR protein. A range of in silico approaches, including molecular dynamics, virtual screening, SIFT analysis, ADMET, DFT, MM/GBSA, MMPBSA and per residue interaction analysis, were performed to identify inhibitors against this protein. The screening of FDA-approved compounds against the BaeR protein yielded 620 compounds. These compounds were clustered by SIFT to distinguish related compounds, it resulted in 20 different clusters. The top five clusters that can accommodate the binding site with better interaction and score by fulfilling all criteria were selected. The DFT analysis showed a smaller energy gap among all the compounds, indicating the ability of the compound to form firm interactions. All the compounds showed less binding free energy in both MM/GBSA and MM/PBSA analyses. The compounds were observed to be stable throughout the simulation. The per-residue interaction analysis confirmed that interactions with binding site residues were stable throughout the simulation. As a result of the study, four compounds, namely ZINC000003801919, DB01203, DB11217 and ZINC0000000056652, were identified as efficient candidates to deal with antimicrobial resistance in A. baumannii.

Pyroptosis, as a lytic-inflammatory type of programmed cell death, has garnered considerable attention due to its role in cancer chemotherapy and many inflammatory diseases. This review will discuss the biochemical classification of pyroptotic inducers according to their chemical structure, pyroptotic mechanism, and cancer type of these targets. A structure-activity relationship study on pyroptotic inducers is revealed based on the surveyed pyroptotic inducer chemotherapeutics. The shared features in the chemical structures of current pyroptotic inducer agents were displayed, including an essential cyclic head, a vital linker, and a hydrophilic tail that is significant for π-π interactions and hydrogen bonding. The presented structural features will open the way to design new hybridized classes or scaffolds as potent pyroptotic inducers in the future, which may represent a solution to the apoptotic-resistance dilemma along with synergistic chemotherapeutic advantage.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC₅₀ of 4.78 ± 0.08 μM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC₅₀ of 0.48 ± 0.02 μM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.

A convenient, straightforward, and effective one-step reaction for the synthesis of a three-component compound of biologically relevant novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno[2,3-b] pyridine-3-carbonitrile derivatives was designed and synthesized. The synthesis was developed by the reaction between salicylaldehyde 1, 8-hydroxyquinoline 2, 2-aminopropene-1,1,3-tricarbonitrile 3, and the catalytic amount of triethylamine in ethanol at 78 °C. This methodology has many beneficial features, including the use of inexpensive and non-hazardous starting materials, single-flask reactions, optimized reaction conditions, the termination of intermediate isolation, easy workup, reducing organic waste products, being chromatography-free, and decreasing the reaction time along with quantitative yields with high functional group tolerance. A proposed mechanism with supporting experimental data is presented, including ¹H NMR, ¹³C NMR, 2D NMR (HMBC, COSY, HSQC), mass, and IR spectroscopy, which are used to characterize the complete derivatives. All synthesized compounds were evaluated in vitro for their antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains via the agar-well diffusion method compared with the reference drug gentamicin. The data indicated that compounds 4A, 4F, 4G, 4 J, and 4K consistently demonstrated strong antimicrobial activity against Gram-positive and Gram-negative bacteria. Furthermore, a molecular docking investigation was carried out to gain insight into the binding mode of the most promising compounds via the crystal structure of the S. aureus DNA gyrase complex with ciprofloxacin (PDB ID: 2XCT). Density functional theory (DFT) calculations were performed to determine the various molecular properties of the synthesized novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno [2,3-b] pyridine-3-carbonitrile derivatives (4A-4 M). On the basis of the reactive sites explored by the molecular electrostatic potential maps, the antibacterial activities of the compounds were screened.

Microwave-assisted protocols have become extensively accepted across various scientific and technological domains because of their numerous advantages, shorter reaction times, higher yields, and often milder reaction conditions. In this review, we focus on the synthesis of N, O, and S-containing heterocyclic structural cores, crucial in the development of pharmaceuticals, agrochemicals, and materials science following through conventional and microwave method via eliminating the side products and enhances the product yield that is nowadays the biggest barrier for a synthetic chemist. The major findings emphasizes the substantial advantages of microwave-assisted techniques over conventional synthetic protocols. This comparative study underscores the potential of microwave-assisted techniques to revolutionize heterocyclic compound synthesis, providing insights into optimizing reaction conditions and expanding the scope of chemical synthesis in industrial applications.

Dengue fever is a significant global public health concern, causing substantial morbidity and mortality worldwide. The disease can manifest in various forms, from mild fever to potentially life-threatening complications. Developing effective treatments remains a critical challenge to healthcare systems. Despite extensive research, no antiviral drugs have been approved for either the prevention or treatment of dengue. Targeting the virus during its early phase of attachment is essential to inhibit viral replication. The capsid protein plays a crucial role in the virus's structural integrity, assembly, and viral genome release. In the present study, we employed a computational approach focused on the capsid protein to identify possible potent inhibitors against the dengue virus from a library of FDA-approved drugs. We employed high-throughput virtual screening on FDA-approved drugs to identify drug molecules that could potentially combat the disease and save both cost and time. The screening process identified four drug molecules (Nordihydroguaiaretic acid, Ifenprodil tartrate, Lathyrol, and Safinamide Mesylate) based on their highest binding affinity and MM/GBSA scores. Among these, Nordihydroguaiaretic acid showed higher binding affinity than the reference molecule with - 11.66 kcal/mol. In contrast, Ifenprodil tartrate and Lathyrol showed similar results to the reference molecule, with binding energies of - 9.42 kcal/mol and - 9.29 kcal/mol, respectively. Following the screening, molecular dynamic simulations were performed to explore the molecular stability and conformational possibilities. The drug molecules were further supported by post-molecular simulation analysis. Furthermore, binding energies were also computed using the MM/GBSA approach, and the free energy landscape was used to calculate the different transition states, revealing that the drugs exhibited significant transition states. Specifically, Nordihydroguaiaretic acid and Ifenprodil tartrate displayed higher flexibility, while Lathyrol and Safinamide Mesylate showed more predictable and consistent protein folding. This significant breakthrough offers new hope against dengue, highlighting the power of computational drug discovery in identifying potent inhibitors and paving the way for novel treatment approaches.