Medicinal Chemistry最新文献

Introduction: Drug targeting and drug discovery methodologies are advancing rapidly due to recent developments in molecular docking techniques. Molecular docking forecasts the interactions between a small molecule, such as a potential medicine, and a target protein or receptor.

Objectives: This comprehensive review focuses on significant advances in molecular docking algorithms such as Vina, Glide, and AutoDock, including their enhanced accuracy and efficiency in predicting drug-target interactions. It also examines how novel features, such as fragment-based docking, covalent docking, and virtual screening, have expanded the significance of docking in modern pharmaceutical research.

Methods: The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as Molecular Docking, Lead-Optimization, Protein Flexibility, Fragment-Based Docking, Covalent Docking, and Virtual Screening.

Results: This present state-of-the-art review highlights recent advances in various docking methodologies and their significant applications in drug discovery, while also discussing the scoring functions of some well-established studies. Furthermore, by predicting the interactions between putative medications and protein residues involved in the creation of covalent bonds, covalent docking provides new opportunities for targeting difficult drug-resistant mutations. The efficiency and precision of these simulations have been increased by improved sampling techniques and sophisticated algorithms, enabling the investigation of conformational changes and protein flexibility throughout the drug-binding process.

Conclusion: These approaches may hasten the course of emerging new remedies, increase the precision of hit-finding, and make it easier to find cutting-edge treatments for a variety of diseases. Molecular docking alone is insufficient to ensure the safety and efficacy of a pharmacological agent for commercialization. While it predicts binding affinity and interaction, it does not account for pharmacokinetics, toxicity, off-target effects, or in vivo behavior. Therefore, experimental validation through MD simulation, ADMET, in vitro, in vivo, and clinical studies is essential.

Introduction: Bacterial diseases pose a significant challenge to modern medicine due to the rapid development of resistance by bacterial strains and the global migration of people, which facilitates the transmission of these diseases. Therefore, there is a need to develop new strategies to combat microorganisms and newer substances that could be used as antibiotics.

Methods: Six new derivatives, 2a-2f, containing a 4-oxybut-2-enoic acid moiety, were obtained by reacting amidrazones with maleic anhydride. The antimicrobial potency of compounds 2a-2f was studied using the microdilution method against the following bacterial strains: Escherichia coli, Yersinia enterocolitica, Pseudomonas aeruginosa, Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis, Gordonia rubripertincta, Mycobacterium smegmatis, and the fungal strain Candida albicans. Their antiproliferative activity was tested in cultures of human peripheral blood mononuclear cells stimulated with phytohemagglutinin. The bioavailability parameters of new compounds were predicted using Molinspiration software.

Results: Derivatives 2a-2c showed the strongest antibacterial activity, especially against Yersinia enterocolitica and Micrococcus luteus. Compounds 2d-2f inhibited the growth of Gordonia rubripertincta. Compounds 2a-2f exhibited low antiproliferative activity towards human peripheral blood mononuclear cells. However, it is necessary to evaluate whether all compounds are well absorbed after oral administration.

Discussion: The most promising antibacterial activity was demonstrated by derivatives possessing a 2-pyridyl substituent at the R1 position (2a-2c) or a phenyl ring at the R² position (2a, 2f).

Conclusion: Compound 2a demonstrated the highest antibacterial activity and selectivity in inhibiting the growth of Y. enterocolitica. Additionally, it exhibited low toxicity to human lymphocytes and demonstrated favorable bioavailability parameters. Therefore, its structure can be used as a starting point for designing new antimicrobials, such as targeted therapies for yersiniosis, beyond traditional antibiotics.

Background: Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers.

Objective: The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins.

Methods: In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands.

Results: A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor.

Conclusion: In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.

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.