Medicinal Chemistry最新文献

Background: The photo-efficacy of oncological phototherapy for both internal and external tumors is encouraging. When light and photochemotherapeutic drugs are applied together, precise cancer targeting, minimal invasiveness, and innovative modes of action are made possible. Current developments in photoactive compounds and new light sources are promising for further advancement.

Objective: When designing photosensitizers, metal complexes may be advantageous since the metal can enhance stability and photocytotoxicity while facilitating their localization and quantification. The absorption spectra of photosensitizers limit their excitation wavelengths, which impact light tissue penetration that differs in various organs. Since longer wavelength light penetrates deeper, PDT is typically carried out at wavelengths greater than 620 nm. Additionally, employing lower intensity (>4-8 J/cm²) energy can greatly lessen the pain and discomfort induced by red-light PDT.

Methods: Low-level laser therapy exposure was used to assess the dithiophosphinic acid complexes' photodynamic treatment efficacy in MCF-7 cells. Following the administration of the complexes at concentrations within IC₅₀ values, red light (4 J, 780 nm) was applied to the cells. Afterward, MCF-7 cells were cultured for 24 hours to evaluate the photodynamic effects of the compounds on cancer cells. Cell viability was assessed using the XTT assay kit.

Results: DTPA complexes have shown effectiveness as photodynamic agents in cancer therapy, with Ni(II) and Ni(II)-pyridine complexes demonstrating significant cytotoxicity against cancer cells.

Conclusion: Light-activated cancer cell therapies are promising, and the synthesized complexes affect the cell cycle and apoptosis-regulating proteins. The compounds can be employed as anticancer agents and a fine starting template for photodynamic drug design.

Currently, the main focus of anticancer drug development and research is to develop anticancer treatment strategies that are both less harmful and more effective. Flavones, a subclass of flavonoids, have shown great promise in the advancement of anticancer drugs because of their strong bioactive properties. Fruits, vegetables, and medicinal plants are abundant sources of these naturally occurring compounds, which have a variety of biological activities such as anti-inflammatory, anti-cancer, and antioxidant properties. Flavones and their derivatives have attracted a lot of attention recently because of their potential to modify significant molecular pathways that are involved in the growth, apoptosis, angiogenesis, and metastasis of cancer cells. The objective of this review is to present a thorough analysis of the chemical makeup of flavone as an anticancer agent. By altering the flavone scaffold's structure, there are beneficial chances to improve its therapeutic qualities, such as its potency, selectivity, and pharmacokinetics. The structural alterations of flavone derivatives that improve their anticancer potency and selectivity are highlighted. Most noteworthy, flavones offer a promising framework for the creation of new anticancer medications, and further research into them may help create more potent and focused cancer treatments.

Background: Acetyl and butyrylcholinesterase are significant enzymes involved in neurological diseases, and the development of more effective inhibitors is crucial for beneficial interference.

Objective: To evaluate the cholinesterase inhibition effect of the synthetic bis-Schiff base compounds and discover the electronic properties as well as binding affinities through computational studies.

Methods: The compounds were synthesized and screened against acetyl and butyrylcholinesterase inhibitory activities in-vitro, while DFT analysis and molecular docking studies were performed for the product compounds.

Results: Seven compounds, including 2a, 2b, 2e, 2c, 2d, 2i, and 2j, exhibited excellent AChE activity, while nine compounds showed potent BChE inhibition compared to galantamine (IC50 = 156.4 ± 1.13 μM). Furthermore, the recent study on molecules 2a-e has provided valuable insights into their mechanism of action as inhibitors of the enzyme ChE, which is crucial for understanding how to regulate this enzyme's activity. Through the use of Time-Dependent Density Functional Theory (TD-DFT), the electronic characteristics of these molecules were meticulously examined, revealing that the Highest Occupied Molecular Orbitals (HOMO) are extensively delocalized across the molecular frameworks of the most active 2a-e compounds. This suggests a significant degree of electron delocalization, which is often associated with chemical reactivity and stability. In comparison to standard galantamine, these compounds demonstrate a lower electrophilicity index, which is indicative of their increased biological efficacy and lower toxicity.

Conclusion: These derivatives showed excellent AChE and BChE activities with favorable electronic properties and superior binding affinities, highlighting their potential as effective inhibitors as therapeutic agents.

Imidazole is believed to be a highly multifunctional compound in the medicinal and biological sectors. This literature focuses on information about the synthesis and anticonvulsant activity presented by the imidazole nucleus. Epilepsy is a chronic brain disorder including multiple seizures and brain cell abnormalities. Due to its old and less effective treatment, with the increase in the number of patients suffering from epilepsy, researchers need to concentrate on the emergence of finding new treatments for epilepsy. Imidazole-containing analogs are found to be significant in the field of medicinal chemistry and the treatment for epilepsy. These studies prompted us to synthesize and provide insights into developing new imidazole-bearing antiepileptic drugs.

Background: Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies. A range of kinase inhibitors, including small molecules and monoclonal antibodies, has been developed. Although early strategies focused on achieving high specificity to minimize adverse effects, resistance to these targeted therapies has limited their effectiveness. As a result, broader-spectrum inhibitors that act on multiple cancer-related kinases are now considered more promising therapeutic options.

Objective: We developed twenty-five new pyrrolopyrimidine derivatives featuring diverse substitution patterns to assess their potential as small-molecule inhibitors of the protein kinases CLK4 and HER2, both of which are significant therapeutic targets in metastatic breast cancer.

Method: Pyrrolopyrimidine derivatives were synthesized and purified by column chromatography. Their protein kinase inhibitory activity was evaluated through a radioactive ATPcompetition assay.

Results: The compounds were obtained through a multi-step synthetic procedure, concluding with substitution reactions. The effects of different substituents on the inhibitory properties of the observed protein kinases are analyzed and discussed.

Conclusion: Aniline-substituted derivatives exhibited the most potent activities, which were further modulated by N-substituted pyrroles. Consequently, we identified both selective and dual inhibitors of the target kinases, demonstrating activity in the nanomolar range.

The G protein-coupled receptor 52 (GPR52) is a Gs-coupled receptor and is located principally in the striatum alongside D₂ receptor and in the pre-frontal cortex alongside D₁ receptor. Its stimulation leads to potentiation of intracellular cAMP levels, producing effects on cAMP levels similar to those of a Gi-coupled D₂ receptor antagonist in the striatum and a Gscoupled D₁ receptor agonist in the prefrontal cortex. This dual mechanism suggests that GPR52 activation could result in antipsychotic effects akin to D₂ antagonism and pro-cognitive effects resembling D₁ agonism. As a result, GPR52 has emerged as a promising therapeutic target for central nervous system (CNS) disorders, including schizophrenia and substance use disorder. Additionally, knocking out (KO) GPR52 not only significantly reduces mutant huntingtin protein (mHTT) levels in the striatum but also rescues Huntington's disease-associated behavioral phenotypes in a knock-in Huntington's disease mouse model, which provides evidence that GRP52 may also serve as a potential target for Huntington's disease. This review summarizes the current state of small-molecule ligand/drug discovery for GPR52, focusing on the latest findings about the role of GPR52 in schizophrenia and Huntington's disease.

Background: The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold.

Objective: This study aimed to screen the synthesized derivatives for their in vitro acetylcholine and butyrylcholinesterase inhibition.

Methods: These compounds were synthesized by refluxing 2,4-dichloro phenylacetic acid with sulfuric acid in ethanol to get the ester, which was further refluxed with thiosemicarbazide in ethanol to get the desired compound (2). Different benzaldehydes were treated with compound (2) in ethanol having a catalytic amount of acetic acid to get thiosemicarbazones.

Results: In the series, seven compounds, including compounds 2c, 2a, 2b, 2d, 2g, 2e, and 2f, displayed excellent acetylcholinesterase inhibition activities in the range of IC₅₀ values from 41.51 ± 3.88 to 95.48 ± 0.70 μM, surpassing than the standard galantamine (IC₅₀ = 104.5 ± 1.20 μM). Also, compounds 2a, 2g, 2h, 2f, 2b, and 2d with IC₅₀ values ranging from 64.47 ± 2.74 to 80.62 ± 0.73 μM exhibited potent inhibition against butyrylcholinesterase enzyme, being similar to the standard galantamine (IC₅₀ = 156.8 ± 1.50 μM). The molecular docking investigation was performed to assess the binding affinity of the compounds with the active site of the enzyme. These compounds, along with the docked complexes, specifically AChE-compound 2a and BuChE-compound 2g, were chosen and subjected to 100-nanosecond molecular dynamics simulations. The simulations demonstrated strong stability of the ligands within the active pockets of AChE and BuChE enzymes.

Conclusion: These derivatives exhibited superior acetylcholinesterase and butyrylcholinesterase inhibitory activities compared to galantamine, with molecular docking and dynamic simulations confirming their strong binding affinity with the active sites of the enzymes.

Introduction: This study presents a comprehensive exploration of the biomedical potential of the synthesized metal-organic framework Zn₄O(BDC)₃, focusing on its applications in cancer and diabetes treatment and its advanced drug delivery capabilities.

Methods: The structural and physicochemical properties of Zn₄O(BDC)₃ were characterized using FTIR, TGA, ¹H NMR, PXRD, and elemental analysis, revealing its exceptional stability and coordination properties. Molecular docking, molecular dynamics simulations (100 ns), and MM-GBSA calculations were performed to assess binding affinities and stability.

Results: The interactions of Zn₄O(BDC)₃ with salmon sperm DNA (SSDNA) and bovine serum albumin (BSA) demonstrated significant anticancer potential, evidenced by binding constant values of 6.0 × 10⁶M^-1 and Gibbs free energy changes of -17.93 and -19.61 kcal/mol, respectively, highlighting its ability to suppress tumor cell proliferation. With doxorubicin (DOX) loading and reloading efficiencies of 88% and 87.5%, Zn₄O(BDC)₃ exhibited superior drug delivery capabilities. The anti-diabetic potential was validated by the formation of human insulin (HI) hexamers with ΔG values of 0.8 ± 0.1 and a significant decrease in absorption intensity (5.8 to 0.05 at 250 nm). Molecular docking studies revealed moderate to high binding affinities (-10.0 to -5.3 kcal/mol) with biomolecular targets, supported by molecular dynamics simulations over 100 ns and MM-GBSA calculations indicating robust stability (ΔG = -33.31 kcal/mol).

Conclusion: These in-silico and in-vitro analyses underscore the significant pharmacological promise of Zn₄O(BDC)₃ as a multifunctional agent for anticancer, antidiabetic, and drug delivery applications.

Objective: Staphylococcus aureus (S. aureus) has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-S. aureus drugs. SecA is a conserved and essential protein in bacteria and is considered as an ideal target for development. Current screening of inhibitors against SecA has focused on the ATP-binding structural domain, which increases the risk of drug side effects, so a novel screening strategy based on the non-ATP-binding structural domain was chosen in this paper.

Methods: A three-dimensional structural model of S. aureus SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential.

Results: The four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA.

Conclusion: In this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of S. aureus drug resistance.