Medicinal Chemistry最新文献

Introduction: The marine habitat is a plentiful source of diverse, active compounds that are extensively utilised for their medicinal properties. Pharmaceutical trends have currently changed towards utilising a diverse range of goods derived from the marine environment.

Method: This study aimed to examine the inhibitory effects of bioactive chemicals derived from marine algae and bacteria. The identification of these compounds was carried out through the process of Gas Chromatography-Mass Spectrometry (GC-MS) profiling. Subsequently, these compounds were subjected to docking simulations against a specific set of target proteins that are known to be frequently overexpressed in three distinct types of cancer.

Result: From the docking results, the ligand 1,4:3,6:5,7-Tribenzal-beta-mannoheptitol was found to be effective against the proteins mTOR (PDB ID: 4JSV) and FGFR2 (PDB ID:6V6Q). The findings of this study highlight the significant benefits offered by the tool under investigation, which effectively enhances the efficiency of the docking procedures.

Conclusion: These compounds hold significant potential for further development and exploration in the field of cancer therapeutics.

Catechins, the main active components of tea polyphenols, boast remarkable antioxidant activities because of their unique structures. This translates to a range of potential health benefits, including fighting antibacterial, inflammation, and even cancers. However, extracting these beneficial compounds can be tricky as they're prone to degradation. Thankfully, recent advancements have yielded successful methods for isolating and purifying catechins, allowing us to obtain them in their purest form. The power of catechins isn't just theoretical. In vitro and in vivo studies have demonstrated promising results in treating various conditions like inflammation, cancer, neurodegenerative diseases, cardiovascular diseases, diabetes, and more. This review dives deep into the methods used to extract, isolate, and purify catechins. Additionally, it explores their potent antioxidant activities and exciting possibilities for future applications.

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.

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.

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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