RESUMO
Structure-activity relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates1-3. Here we present an alternative approach in which we convert pyrimidine-containing compounds into various other nitrogen heteroaromatics. Transforming pyrimidines into their corresponding N-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles4. In effect, this approach allows heterocycle formation on complex molecules, resulting in analogues that would be challenging to obtain by other methods. We anticipate that this deconstruction-reconstruction strategy will extend to other heterocycle classes.
Assuntos
Técnicas de Química Sintética , Pirimidinas , Azóis/química , Nitrogênio/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Técnicas de Química Sintética/métodosRESUMO
The medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.
Assuntos
Antineoplásicos , Azóis , Compostos Ferrosos , Compostos Heterocíclicos , Metalocenos , Azóis/química , Azóis/farmacologia , Azóis/síntese química , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Ferrosos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Metalocenos/química , Metalocenos/farmacologia , Metalocenos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese químicaRESUMO
The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (Mpro). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the Mpro catalytic site. Ebselen effectively engaged the active site, adopting proximity to H41 and interacting through the benzoisoselenazole ring in a π-π T-shaped arrangement, with an additional π-sulfur interaction with C145. In addition, the ligand-based drug design using the QSAR with GFA-MLR, RF, and ANN models were employed for biological activity prediction. The QSAR-ANN model showed robust statistical performance, with an r2training exceeding 0.98 and an RMSEtest of 0.21, indicating its suitability for predicting biological activities. Integration the ANN model with the LB-PaCS-MD insights enabled the rational design of novel compounds anchored in the ebselen core structure, identifying promising candidates with favorable predicted IC50 values. The designed compounds exhibited suitable drug-like characteristics and adopted an active conformation similar to ebselen, inhibiting Mpro function. These findings represent a synergistic approach merging ligand and structure-based drug design; with the potential to guide experimental synthesis and enzyme assay testing.
Assuntos
Antivirais , Proteases 3C de Coronavírus , Desenho de Fármacos , Isoindóis , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Compostos Organosselênicos , Inibidores de Proteases , Relação Quantitativa Estrutura-Atividade , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Isoindóis/química , Isoindóis/farmacologia , Isoindóis/síntese química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/síntese química , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Azóis/química , Azóis/farmacologia , Azóis/síntese química , COVID-19/virologia , Domínio CatalíticoRESUMO
Favipiravir (FP) and ebselen (EB) belong to a diverse class of antiviral drugs known for their significant efficacy in treating various viral infections. Utilizing molecular dynamics (MD) simulations, machine learning, and van der Waals density functional theory, we accurately elucidate the binding properties of these antiviral drugs on a phosphorene single-layer. To further investigate these characteristics, this study employs four distinct machine learning models-Random Forest, Gradient Boosting, XGBoost, and CatBoost. The Hamiltonian of antiviral molecules within a monolayer of phosphorene is appropriately trained. The key aspect of utilizing machine learning (ML) in drug design revolves around training models that are efficient and precise in approximating density functional theory (DFT). Furthermore, the study employs SHAP (SHapley Additive exPlanations) to elucidate model predictions, providing insights into the contribution of each feature. To explore the interaction characteristics and thermodynamic properties of the hybrid drug, we employ molecular dynamics and DFT calculations in a vacuum interface. Our findings suggest that this functionalized 2D complex exhibits robust thermostability, indicating its potential as an effective and enabled entity. The observed variations in free energy at different surface charges and temperatures suggest the adsorption potential of FP and EB molecules from the surrounding environment.
Assuntos
Antivirais , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Antivirais/química , Antivirais/farmacologia , Teoria da Densidade Funcional , Termodinâmica , Isoindóis/química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Azóis/química , Azóis/farmacologiaRESUMO
While research has identified several inhibitors of the main protease (Mpro) of SARS-CoV-2, a significant portion of these compounds exhibit reduced activity in the presence of reducing agents, raising concerns about their effectiveness in vivo. Furthermore, the conventional biosafety level 3 (BSL-3) for cellular assays using viral particles poses a limitation for the widespread evaluation of Mpro inhibitor efficacy in a cell-based assay. Here, we established a BSL-1 compatible cellular assay to evaluate the in vivo potential of Mpro inhibitors. This assay utilizes mammalian cells expressing a tagged Mpro construct containing N-terminal glutathione S-transferase (GST) and C-terminal hemagglutinin (HA) tags and monitors Mpro autodigestion. Using this method, GC376 and boceprevir effectively inhibited Mpro autodigestion, suggesting their potential in vivo activity. Conversely, carmofur and ebselen did not exhibit significant inhibitory effects in this assay. We further investigated the inhibitory potential of selenoneine on Mpro using this approach. Computational analyses of binding energies suggest that noncovalent interactions play a critical role in facilitating the covalent modification of the C145 residue, leading to Mpro inhibition. Our method is straightforward, cost-effective, and readily applicable in standard laboratories, making it accessible to researchers with varying levels of expertise in infectious diseases.
Assuntos
Antivirais , Azóis , Proteases 3C de Coronavírus , Isoindóis , Compostos Organosselênicos , Prolina , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/química , Isoindóis/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Azóis/farmacologia , Azóis/química , Prolina/análogos & derivados , Prolina/farmacologia , Prolina/química , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Tratamento Farmacológico da COVID-19 , COVID-19/virologia , Células HEK293 , Lactamas , Leucina/análogos & derivados , Ácidos SulfônicosRESUMO
The wheat scab caused by Fusarium graminearum (F. graminearum) has seriously affected the yield and quality of wheat in China. In this study, gallic acid (GA), a natural polyphenol, was used to synthesize three azole-modified gallic acid derivatives (AGAs1-3). The antifungal activity of GA and its derivatives against F. graminearum was studied through mycelial growth rate experiments and field efficacy experiments. The results of the mycelial growth rate test showed that the EC50 of AGAs-2 was 0.49 mg/mL, and that of AGAs-3 was 0.42 mg/mL. The biological activity of AGAs-3 on F. graminearum is significantly better than that of GA. The results of field efficacy tests showed that AGAs-2 and AGAs-3 significantly reduced the incidence rate and disease index of wheat scab, and the control effect reached 68.86% and 72.11%, respectively. In addition, preliminary investigation was performed on the possible interaction between AGAs-3 and F. graminearum using density functional theory (DFT). These results indicate that compound AGAs-3, because of its characteristic of imidazolium salts, has potential for use as a green and environmentally friendly plant-derived antifungal agent for plant pathogenic fungi.
Assuntos
Antifúngicos , Azóis , Fusarium , Ácido Gálico , Triticum , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Ácido Gálico/química , Ácido Gálico/farmacologia , Antifúngicos/farmacologia , Antifúngicos/química , Triticum/microbiologia , Azóis/farmacologia , Azóis/química , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Testes de Sensibilidade MicrobianaRESUMO
The global occurrence of micropollutants in water bodies has raised concerns about potential negative effects on aquatic ecosystems and human health. EU regulations to mitigate such widespread pollution have already been implemented and are expected to become increasingly stringent in the next few years. Catalytic wet peroxide oxidation (CWPO) has proved to be a promising alternative for micropollutant removal from water, but most studies were performed in batch mode, often involving complex, expensive, and hardly recoverable catalysts, that are prone to deactivation. This work aims to demonstrate the feasibility of a fixed-bed reactor (FBR) packed with natural magnetite powder for the removal of a representative mixture of azole pesticides, recently listed in the EU Watch Lists. The performance of the system was evaluated by analyzing the impact of H2O2 dose (3.6-13.4 mg L-1), magnetite load (2-8 g), inlet flow rate (0.25-1 mL min-1), and initial micropollutant concentration (100-1000 µg L-1) over 300 h of continuous operation. Azole pesticide conversion values above 80% were achieved under selected operating conditions (WFe3O4 = 8 g, [H2O2]0 = 6.7 mg L-1, flow rate = 0.5 mL min-1, pH0 = 5, T = 25 °C). Notably, the catalytic system showed a high stability upon 500 h in operation, with limited iron leaching (< 0.1 mg L-1). As a proof of concept, the feasibility of the system was confirmed using a real wastewater treatment plant (WWTP) effluent spiked with the mixture of azole pesticides. These results represent a clear advance for the application of CWPO as a tertiary treatment in WWTPs and open the door for the scale-up of FBR packed with natural magnetite.
Assuntos
Óxido Ferroso-Férrico , Praguicidas , Poluentes Químicos da Água , Catálise , Poluentes Químicos da Água/química , Óxido Ferroso-Férrico/química , Peróxido de Hidrogênio/química , Oxirredução , Azóis/químicaRESUMO
Background: Azole and sulfonamide molecular frameworks are endowed with potent antimicrobial activity. Materials & methods: A series of azole-sulfonamide conjugates were synthesized using click reaction of N-propargylated imidazole with azide of sulfonamide and its antimicrobial efficacy was evaluated. Results: The compounds 7c, 7i and 7r displayed promising antibacterial activities, better than the standards sulfonamide and norfloxacin. All molecules exhibited promising antifungal activity, more potent than fluconazole. Docking studies of the active conjugates signified the importance of hydrophobic interactions in hosting the molecules in the active site of dihydrofolate reductase. Conclusion: Azole-sulfonamide conjugates are more active than single sulfonamide moieties and 7c, 7i and 7r may prove valuable leads for further optimization as novel antimicrobial agents.
Assuntos
Antibacterianos , Azóis , Azóis/química , Antibacterianos/química , Antifúngicos/química , Fluconazol , Sulfanilamida , Sulfonamidas/farmacologia , Sulfonamidas/química , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade MicrobianaRESUMO
During the last decades, five or six member rings azaheterocycles compounds appear to be an extremely valuable source of antifungal agents. Their use seems to be a very attractive solution in antifungal therapy and to overcome antifungal resistance in agriculture. The present review highlights the main results obtained in the field of hybrid and chimeric azine (especially pyridine, quinoline, phenanthroline, bypyridine, naphthyridine and their fused derivatives) derivatives presented in scientific literature from the last 10 years, with emphasis on antifungal activity of the mentioned compounds. A special attention was played to hybrid and chimeric azole-azine class, having in view the high antifungal potential of azoles.
[Box: see text].
Assuntos
Antifúngicos , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/síntese química , Humanos , Azóis/química , Azóis/farmacologia , Azóis/síntese química , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Fungos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Quinolinas/química , Quinolinas/farmacologiaRESUMO
Cancer exhibits heterogeneity that enables adaptability and remains grand challenges for effective treatment. Chemotherapy is a validated and critically important strategy for the treatment of cancer, but the emergence of multidrug resistance which may lead to recurrence of disease or even death is a major hurdle for successful chemotherapy. Azoles and sulfonamides are important anticancer pharmacophores, and azole-sulfonamide hybrids have the potential to simultaneously act on dual/multiple targets in cancer cells, holding great promise to overcome drug resistance. This review outlines the current scenario of azole-sulfonamide hybrids with the anticancer potential, and the structure-activity relationships as well as mechanisms of action are also discussed, covering articles published from 2020 onward.
[Box: see text].
Assuntos
Antineoplásicos , Azóis , Neoplasias , Sulfonamidas , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Azóis/química , Azóis/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Candida albicans and C. glabrata express exporters of the ATP-binding cassette (ABC) superfamily and address them to their plasma membrane to expel azole antifungals, which cancels out their action and allows the yeast to become multidrug resistant (MDR). In a way to understand this mechanism of defense, we describe the purification and characterization of Cdr1, the membrane ABC exporter mainly responsible for such phenotype in both species. Cdr1 proteins were functionally expressed in the baker yeast, tagged at their C-terminal end with either a His-tag for the glabrata version, cgCdr1-His, or a green fluorescent protein (GFP) preceded by a proteolytic cleavage site for the albicans version, caCdr1-P-GFP. A membrane Cdr1-enriched fraction was then prepared to assay several detergents and stabilizers, probing their level of extraction and the ATPase activity of the proteins as a functional marker. Immobilized metal-affinity and size-exclusion chromatographies (IMAC, SEC) were then carried out to isolate homogenous samples. Overall, our data show that although topologically and phylogenetically close, both proteins display quite distinct behaviors during the extraction and purification steps, and qualify cgCdr1 as a good candidate to characterize this type of proteins for developing future inhibitors of their azole antifungal efflux activity.
Assuntos
Antifúngicos , Azóis , Candida albicans , Farmacorresistência Fúngica , Proteínas Fúngicas , Proteínas de Membrana Transportadoras , Azóis/farmacologia , Azóis/química , Azóis/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/isolamento & purificação , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Candida albicans/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Candida glabrata/efeitos dos fármacos , Candida glabrata/genética , Candida glabrata/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/químicaRESUMO
Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.
Assuntos
Compostos de Bifenilo , Lignanas , Micelas , Compostos Organosselênicos , Traumatismo por Reperfusão , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/tratamento farmacológico , Compostos de Bifenilo/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Lignanas/química , Lignanas/administração & dosagem , Humanos , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/administração & dosagem , Isoindóis/farmacologia , Isoindóis/administração & dosagem , Isoindóis/química , Apoptose/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/administração & dosagem , Azóis/química , Azóis/farmacologia , Azóis/administração & dosagem , Animais , Rim/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/administração & dosagem , Tamanho da Partícula , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Portadores de Fármacos/química , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVE: This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized. METHOD: The novel emodin alkyl azoles were synthesized using commercial emodin and azoles by alkylation. The NMR and HRMS spectra were employed to confirm the structures of novel prepared compounds. The in vitro antibacterial and antifungal activities of the prepared emodin compounds were studied by the 96-well plate method. The binding behavior between emodin 4-nitro imidazole compound 3c and S. aureus DNA was researched using an ultraviolet-visible spectrophotometer. Furthermore, fluorescence spectrometry was used to explore the interaction with human serum albumin (HSA). RESULTS: The in vitro antimicrobial results displayed that compound 3c gave relatively strong activities with MIC values of 4-16 µg/mL. Notably, this compound exhibited 2-fold more potent activity against S. aureus (MIC = 4 µg/mL) and E. coli (MIC = 8 µg/mL) strains than clinical drug Chloromycin (MIC = 8 and 16 µg/mL). The UV-vis absorption spectroscopy showed that 4-nitro imidazole emodin 3c could form the 3c-DNA complex by intercalating into S. aureus DNA, inhibiting antimicrobial activities. The simulation results displayed that the emodin 3c and DNA complex were formed by hydrogen bonds. The spectral experiment demonstrated that compound 3c could be transported by human serum albumin (HSA) via hydrogen bonds. The molecular simulation found that the hydroxyl group and the nitroimidazole ring of the emodin compound showed an important role in transportation behavior. CONCLUSION: This work may supply useful directions for the exploration of novel antimicrobial agents.