Medicinal Chemistry最新文献

Background: We continue to struggle with the prevention and treatment of the influenza virus. The 2009 swine flu pandemic, caused by the H1N1 strain of influenza A, resulted in numerous fatalities. The threat of influenza remains a significant concern for global health, and the development of novel drugs targeting these viruses is highly desirable.

Objective: The objective of this study is to explore the inhibitory potential of terpenoid compounds against the Nucleoprotein (NP) of influenza A virus, which is a highly effective drug target due to its ability to facilitate the transcription and replication of viral RNA.

Method: In silico research was performed to identify potential inhibitors of NP. Molecular docking studies were conducted to assess the binding of terpenoid compounds to the active site residues of the target protein. The most promising hits were then subjected to molecular dynamics simulations to examine the stability of the protein-ligand complexes. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies and Lipinski's rule of five were employed to evaluate the drug safety and druglikeness of the compounds.

Result: Docking studies revealed that the terpenoid compounds bind strongly to the active site residues of the NP protein. Molecular dynamics simulations demonstrated the stability of the proteinligand complexes for the best-hit compounds. ADMET studies and Lipinski's filter indicated that the compounds exhibit desirable drug safety and drug-likeness profiles.

Conclusion: This work may contribute significantly to drug discovery and the development of therapeutic agents against the influenza A virus. The identification of terpenoid compounds that bind strongly to the NP protein and exhibit favorable drug-like properties through in silico studies provides a promising foundation for further research and the development of potential inhibitors targeting this critical viral protein.

Background: Overexpression of HDAC8 was observed in various cancers and inhibition of HDAC8 has emerged as a promising therapeutic approach in recent decades.

Objective: This review aims to facilitate the discovery of novel selective HDAC8 inhibitors by analyzing the structural scaffolds of 66 known selective HDAC8 inhibitors, along with their IC50 values against HDAC8 and other HDACs.

Methods: The inhibitors were clustered based on structural symmetry, and common pharmacophores for each cluster were identified using Phase. Molecular docking with all HDACs was performed to determine binding affinity and crucial interacting residues for HDAC8 inhibition. Representative inhibitors from each cluster were subjected to molecular dynamics simulation to analyze RMSD, RMSF, active site amino acid residues, and crucial interacting residues responsible for HDAC8 inhibition. The study reviewed the active site amino acid information, active site cavities of all HDACs, and the basic structure of Zn²⁺ binding groups.

Results: Common pharmacophores identified included AADHR_1, AADDR_1, ADDR_1, ADHHR_1, and AADRR_1. Molecular docking analysis revealed crucial interacting residues: HIS- 142, GLY-151, HIS-143, PHE-152, PHE-208 in the main pocket, and ARG-37, TYR-100, TYR- 111, TYR-306 in the secondary pocket. The RMSD of protein and RMSF of active site amino acid residues for stable protein-ligand complexes were less than 2.4 Å and 1.0 Å, respectively, as identified from MD trajectories. The range of Molecular Mechanics Generalized Born Surface Area (MM-GBSA) ΔG predicted from MD trajectories was between -15.8379 Å and -61.5017 Å kcal/mol.

Conclusion: These findings may expedite the rapid discovery of selective HDAC8 inhibitors subject to experimental evaluation.

Introduction: Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase.

Methods: A set of 4,6-dihydroxyaurone derivatives, each with varied substituent patterns on ring B, were designed and subjected to computational studies to predict their binding affinity, binding modes with tyrosinase, and drug-likeness properties. These aurone derivatives were subsequently synthesized and evaluated in vitro for their tyrosinase inhibitory activity. Enzyme kinetics studies were conducted to determine the mode of tyrosinase inhibition.

Results: Computational studies of the twenty designed aurone derivatives indicated their strong binding within the active site and exhibited favorable drug-likeness properties. In vitro UV-Vis spectrophotometric assays of the synthesized compounds revealed that compound 5h, featuring a 3,4-dichlorophenyl substituent on ring B, showed the most potent tyrosinase inhibitory activity (IC₅₀ = 6.3 ± 0.3 μM) compared to kojic acid (IC₅₀ = 136.5 ± 11.5 μM). Kinetic studies and molecular docking simulations indicated that compound 5h inhibits tyrosinase through a mixedtype inhibition mechanism, with competitive and uncompetitive inhibition constants of 21 μM and 68 μM, respectively.

Conclusion: These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.

Aims: In this current study, a new series of triazolo-triazine derivatives were designed and synthesized as potential anticancer agents.

Methods: The antiproliferative activity of the new compounds was evaluated against four different cancerous cell lines (MDA-MB-231, HCT-116, A549, and HT-29) using an MTT assay. To evaluate the mechanism of action, the ability of the best compound in apoptosis induction and DNA damage was evaluated using the flow cytometry technique and comet assays. Furthermore, molecular docking simulation was used to investigate their interactions with the two targets, VEGFR2 and c-Met kinases.

Results: Results showed that 6-(4-bromophenyl)-3-((4-methoxybenzyl)thio)-[1,2,4]triazolo[4,3- b][1,2,4]triazine (8c) demonstrated the best anti-proliferative activity against the human colorectal carcinoma cells HCT-116 with an IC₅₀ value of 38.7 ± 1.7 μM. In silico evaluations showed that the triazolo-triazine scaffold, along with the methoxy substitution of compound 8c, was involved in creating effective H-bond interactions in the active site of both targets.

Conclusion: Our results showed that compound 8c significantly increased cell death through apoptosis induction and caused a significant increase in genotoxicity. Furthermore, it was found that the tested compound 8c, with a selectivity index of 1.74, possessed selective antiproliferative activity towards the colorectal cancer cell line HCT-116 compared to the normal fibroblast cell line. These findings could be useful in the development of novel VEGFR2/c-Met dual-targeted inhibitors in the future.

Background: In many types of cancer, uncontrolled growth and proliferation of cells occur due to abnormalities in their genes, mutations of pro-apoptotic proteins, or upregulation of anti-apoptotic proteins. Triazolinedione and pyrrole derivatives are compounds with anti-microbial, anti-fungal, anti-inflammatory, and anti-cancer activities. Pyrrole and its derivatives are critical heterocycle compounds that are significant in anticancer studies and highly preferred in research.

Objective: This study aimed to investigate the effects of dihydropyrrole derivatives substituted with triazolinedione on the MCF-7 (breast cancer) cell line's apoptosis, ER stress, and heat shock genes.

Methods: The mRNA levels of apoptosis, ER stress, and heat shock proteins were assessed by qRT-PCR method in the MCF-7 cell line. The investigation of ADMET features, crucial pharmacokinetic indices for the potential candidacy of compounds as drugs, has been meticulously designed. In silico-induced molecular docking studies were conducted to further explore the interaction and elucidate the orientation of hybrid compounds within the active sites of BCL-2, PARP, HSP70, HSP90, and GRP78.

Results: It was determined that the compounds caused cell death by modulating apoptotic (compound IV), ER stress, and heat shock proteins (compounds XI and XVI) through up- and downregulation. Our findings have pointed to the effects of triazolinedione-substituted dihydropyrrole derivatives, exhibiting antitumor activity on apoptosis, ER stress, and heat shock genes in the MCF- 7 cell line.

Conclusion: The compounds investigated in this study have been found to be promising for anticancer research.

Introduction/objective: Biguanide derivatives are small molecules with promising antitumor activity. However, the effect of different carbon rings at the end of one guanide group of these compounds on anti-proliferation activity is unknown. Therefore, we synthesized novel fluorine- containing biguanide compounds with various carbon rings, evaluated their anticancer activities, and explored their anti-proliferative mechanisms.

Methods: Guanidine derivatives containing trifluoromethoxy or 3,4-difluorophenyl with nine different carbon rings were synthesized using established chemical methods. The phenyl side chain was fixed to trifluoromethoxy or 3,4-difluorophenyl with changes in the number of cyclic aminocyclic carbons. The effects of these derivatives were evaluated using MTT and clonogenic assays, while the underlying mechanisms were investigated by analyzing protein expression levels via western blotting.

Results: This study analyzed the effects of new biguanide derivatives on cell growth in three different cell lines: HepG2, Ovcar3, and T24. The results showed that T24 cells were the most sensitive cell line to these biguanides. All biguanide derivatives significantly inhibited the growth of T24 cells, while compound 4b exhibited the strongest inhibition in all three cell lines by MTT assay. The inhibitory effects of 4b were further confirmed using colony formation experiments. Western blotting results indicated that the representative biguanide derivative, 4b, inhibited the EGFR signaling pathway, thereby inhibiting tumor growth.

Conclusion: 1a-5a and 1b-4b, the cyclooctyl-containing 3,4-difluorophenyl biguanide analogs, have demonstrated significant potential in developing novel anticancer drugs. The 3,4- difluorophenyl biguanide containing cyclooctyl showed the best antitumor activity among the nine derivatives. This finding offers a novel perspective in developing anticancer drugs and a further improvement in biguanide activity in the future.

Pyridazinone, a six-membered heterocyclic molecule, has emerged as an important pharmacophore in drug discovery due to its diverse range of biological actions. This adaptable scaffold has shown tremendous promise in the development of therapeutic medicines for a variety of pharmacological conditions, including anti-inflammatory, anti-cancer, anti-microbial, cardiovascular, and central nervous system illnesses. Pyridazinone derivatives are useful in medicinal chemistry due to their propensity to interact with a wide range of biological targets. This review offers a comprehensive overview of Pyridazinone-based compounds, focusing on their chemical structure, mechanism of action, structure-activity relationship (SAR), and therapeutic uses. Current trends in Pyridazinone research and its potential as a lead chemical for new medication development are also reviewed. Pyridazinone broad range of activity and adaptability highlight its importance in developing pharmacotherapy.

The 2-isoxazoline scaffold has emerged as a key structure in medicinal chemistry, with great therapeutic potential for a wide range of biological targets. This review investigates the medicinal value of the 2-isoxazoline scaffold, emphasizing its adaptability and usefulness in the development of new medications. Isoxazoline has a wide range of biological actions, including antibacterial, anti-inflammatory, anticancer, and anti-parasitic effects, which are due to their distinct structural features and capacity to interact with a variety of biological processes. The synthesis, functionalization, and pharmacological uses of isoxazoline derivatives are rigorously studied, yielding information about their modes of action and therapeutic value. This review emphasizes the promise of isoxazoline-based molecules in tackling current medical difficulties and lays the way for future research in this vibrant field of medicinal chemistry.

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Aim: There is an urgent need for new antimicrobial compounds with alternative modes of action for the treatment of drug-resistant bacterial and fungal pathogens.

Background: Carbohydrates and their derivatives are essential for biochemical and medicinal research because of their efficacy in the synthesis of biologically active drugs.

Objective: In the present study, a series of methyl α-D-mannopyranoside (MMP) derivatives (2-6) were prepared via direct acylation, and their biological properties were characterized.

Methods: The structures of synthesized compounds were established by analyzing their physicochemical, elemental, and spectroscopic data and evaluating their in vitro antimicrobial activities through in silico studies.

Results: In the antibacterial study, compound 3 was found to be mostly active toward most of the organisms, exhibiting maximum inhibition of S. abony and minimum inhibition of P. aeruginosa. However, the MIC and MBC values revealed that this compound is highly effective against Bacillus subtilis (MIC of 0.5 μg/L and MBC of 256 μg/L). In terms of antifungal activity, 3 and 6 showed the most promising activity toward Aspergillus flavus, with an inhibition of 95.90 ± 1.0% for compound 3 and 96.72 ± 1.1% for compound 6. Moreover, density functional theory (DFT) in conjunction with the BLYP/6-311G (d) basis sets was used to calculate the dipole moment and total energy for each compound, and the molecular electrostatic potential and Mulliken charge were considered to study the electrophilicity and nucleophilicity of the groups in each compound. For dipole moment calculations, the dipole moments are in the following order: 6 < 3 < 1 < 5 < 2 < 4, inferring that compounds 2 and 4 possess a high dipole moment in comparison with the other inhibitor systems. Furthermore, molecular docking was performed against threonine synthase from B. subtilis ATCC 6633 (PDB: 6CGQ) to identify the active site of the compounds, with compound 3 showing a maximum binding energy of -10.3 kcal/mol and compound 4 exhibiting a binding energy of -10.2 kcal/mol. In addition, a 100 ns MD simulation was performed, and the results revealed a stable conformation and binding pattern within the stimulating environment.

Conclusion: Our synthetic, antimicrobial, and in silico experiments revealed that MMP derivatives exhibit potential activity, providing a therapeutic target for bacteria and fungi.