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High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new click able building blocks remain exceedingly challenging. Here in , we describe a double-click strategy that enables the sequential ligation of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO 2 NCO) via a modular amidation/SuFEx process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO 2 F) and N-acylsulfamides (RCONHSO 2 NR ´ R ´´ ) in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compound s exhibit high antimicrobial activities against Gram-positive bacterium S. aureus and drug-resistant MRSA (MIC up to 6.25·µg mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.
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An efficient silver-mediated oxidative trifluoromethylthiolation of unsaturated carboxylic acids to construct trifluoromethylthiol-containing lactones has been disclosed. In this protocol no metal-catalysts was added, and preliminary mechanism investigations suggested that a free-radical pathway should be involved in the process. High functional group tolerance and excellent yields were demonstrated by the efficient preparation of a wide range of γ-trifluoromethylthiolated phthalides.
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A copper-catalyzed direct C-H chalcogenation of N-aryl-azaindoles with disulfides is described. This transformation was performed using Earth abundant Cu(OAc)2 as a catalyst, benzoic acid as an additive, air as a terminal oxidant, and readily available diaryl and dialkyldisulfides (or diselenide) as chalcogenation reagents. High functional group tolerance and excellent regioselectivity are demonstrated by the efficient preparation of a wide range of ortho-sulfenylation-7-azaindoles.
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Copper-catalyzed difunctionalization of 2-vinylbenzoic acids with sodium sulfinates to construct substituted lactones has been realized. This protocol employs inexpensive CuCl2 as the catalyst, di-tert-butyl peroxide or O2 as the terminal oxidant, and readily available sodium sulfinates as sulfonylation reagents. High functional group tolerance and excellent yields were demonstrated by the efficient preparation of a wide range of γ-sulfonylated phthalides.
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Quaternization of ruthenium complexes may be a promising strategy for the development of new antibiotics. In response to the increasing bacterial resistance, we integrated the quaternary amine structure into the design of ruthenium complexes and evaluated their antibacterial activity. All the ruthenium complexes showed good antibacterial activity against the tested Staphylococcus aureus (S. aureus). Ru-8 was the most effective antibacterial agent that displayed excellent antibacterial activity against S. aureus (MIC = 0.78-1.56 µg/mL). In vitro experiments showed that all nine ruthenium complexes had low hemolytic toxicity to rabbit erythrocytes. Notably, Ru-8 was found to disrupt bacterial cell membranes, alter their permeability, and induce ROS production in bacteria, all the above leading to the death of bacteria without inducing drug resistance. To further explore the antibacterial activity of Ru-8in vivo, we established a mouse skin wound infection model and a G. mellonella larvae infection model. Ru-8 exhibited significant antibacterial efficacy against S. aureus in vivo and low toxicity to mouse tissues. The Ru-8 showed low toxicity to Raw264.7 cells (mouse monocyte macrophage leukemia cells). This study indicates that the ruthenium complex ruthenium quaternary was a promising strategy for the development of new antibacterial agents.
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Developing new antimicrobials to combat drug-resistant bacterial infections is necessary due to the increasing problem of bacterial resistance. In this study, four metallic ruthenium complexes modified with benzothiazoles were designed, synthesized and subjected to bio-evaluated. Among them, Ru-2 displayed remarkable inhibitory activity against Staphylococcus aureus (S. aureus) with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. Additionally, it showcased low hemolytic toxicity (HC50 > 200 µg/mL) and the ability to effectively eradicate S. aureus without fostering drug resistance. Further investigation into the antibacterial mechanism suggested that Ru-2 may target the phospholipid component of S. aureus, leading to the disruption of the bacterial cell membrane and subsequent leakage of cell contents (nucleic acid, protein, and ONPG), ultimately resulting in the death of the bacterial cell. In vivo studies, both the G. mellonella larvae and the mouse skin infection models were conducted, indicated that Ru-2 could potentially serve as a viable candidate for the treatment of S. aureus infection. It exhibited no toxic or side effects on normal tissues. The results suggest that benzothiazole-modified ruthenium complexes may have potential as membrane-active antimicrobials against drug-resistant bacterial infections.
Assuntos
Anti-Infecciosos , Infecções Bacterianas , Complexos de Coordenação , Staphylococcus aureus Resistente à Meticilina , Rutênio , Animais , Camundongos , Staphylococcus aureus , Rutênio/farmacologia , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Benzotiazóis/farmacologia , Complexos de Coordenação/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Compounds modified with selenium atom as potential antibacterial agents have been exploited to combat the nondrug-resistant bacterial infection. In this study, we designed and synthesized four ruthenium complexes retouching of selenium-ether. Fortunately, those four ruthenium complexes shown excellent antibacterial bioactive (MIC: 1.56-6.25 µg/mL) against Staphylococcus aureus (S. aureus), and the most active complex Ru(II)-4 could kill S. aureus by targeting the membrane integrity and avoid the bacteria to evolve drug resistance. Moreover, Ru(II)-4 was found to significantly inhibit the formation of biofilms and biofilm eradicate capacity. In toxicity experiments, Ru(II)-4 exhibited poor hemolysis and low mammalian toxicity. To illustrate the antibacterial mechanism: we conducted scanning electron microscope (SEM), fluorescent staining, membrane rupture and DNA leakage assays. Those results demonstrated that Ru(II)-4 could destroy the integrity of bacterial cell membrane. Furthermore, both G. mellonella wax worms infection model and mouse skin infection model were established to evaluate the antibacterial activity of Ru(II)-4 in vivo, the results indicated that Ru(II)-4 was a potential candidate for combating S. aureus infections, and almost non-toxic to mouse tissue. Thus, all the results indicated that introducing selenium-atom into ruthenium compounds were a promising strategy for developing interesting antibacterial agents.
Assuntos
Complexos de Coordenação , Infecções por Bactérias Gram-Positivas , Rutênio , Selênio , Animais , Camundongos , Staphylococcus aureus , Rutênio/farmacologia , Complexos de Coordenação/farmacologia , Selênio/farmacologia , Antibacterianos/farmacologia , Bactérias , Resistência a Medicamentos , Testes de Sensibilidade Microbiana , MamíferosRESUMO
Bacterial infection is one of the most serious public health problems, being harmful to human health and expensive. Nowadays, the misuse and overuse of antibiotics have led to the emergence of drug resistance. Therefore, it is an urgent need to develop new antimicrobial agents to address the current situation. In this study, four 1,2,4-triazole ruthenium polypyridine complexes [Ru(bpy)2(TPIP)](PF6)2 (Ru1), [Ru(dmb)2(TPIP)](PF6)2 (Ru2), [Ru(dtb)2(TPIP)](PF6)2 (Ru3) and [Ru(dmob)2(TPIP)](PF6)2 (Ru4) (bpy = 2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, dmob = 4,4'-dimethoxy-2,2'-bipyridine and TPIP = 2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and evaluated for antibacterial activity. Results showed that the minimum inhibitory concentration (MIC) value of Ru3 against Staphylococcus aureus (S. aureus) was only 0.78 µg mL-1, showing the best antimicrobial activity in vitro. Besides, Ru3 showed low hemolytic activity and good biocompatibility. Due to its ability to damage the cell membrane of Staphylococcus bacteria, Ru3 was able to kill bacteria in a short time. Importantly, by inhibiting bacterial toxins and the formation of biofilm, Ru3 was not susceptible to the development of drug resistance. Moreover, Ru3 revealed excellent therapeutic effects in vivo and showed no irritation to the skin of mice. In conclusion, the four obtained 1,2,4-triazole ruthenium polypyridine complexes show strong antibacterial activity and satisfactory biocompatibility with excellent potential for antibacterial treatment, and provide a new solution for the current antibacterial crisis.
Assuntos
Antineoplásicos , Complexos de Coordenação , Rutênio , Camundongos , Animais , Humanos , Staphylococcus aureus , Rutênio/farmacologia , Antibacterianos/farmacologia , 2,2'-Dipiridil/farmacologia , Complexos de Coordenação/farmacologia , Antineoplásicos/farmacologiaRESUMO
Antibiotic abuse has caused the generation of drug-resistant bacteria and a series of infections induced by multidrug-resistant bacteria have become a threat to human health. Facing the failure of traditional antibiotics, antibacterial drugs with new molecular and action modes urgently need to be developed. In this study, ruthenium complexes containing coumarin were designed and synthesized. By altering the structure of the ancillary ligand, we explored the biological activities of four ruthenium complexes against Staphylococcus aureus. Among them, Ru(II)-1 with the best antibacterial activity (minimum inhibitory concentration: 1.56 µg mL-1) was used for further investigations. Surprisingly, Ru(II)-1 could significantly inhibit the formation of biofilm and hinder the development of drug-resistant bacteria. Besides, Ru(II)-1 also exhibited excellent biocompatibility. Antibacterial mechanism studies suggested that Ru(II)-1 could target the bacterial cell membrane and combine with the phospholipid component of the membrane (phosphatidylglycerol and phosphatidylethanolamine) and generate reactive oxygen species to induce an oxidative stress response, which resulted in the damage of membrane integrity, finally leading bacteria death. Moreover, antibacterial tests in G. mellonella larvae and mice in vivo model indicated that Ru(II)-1 had the potential to combat S. aureus infection. Therefore, all the above results showed that ruthenium complexes modified with coumarin could be a promising antibacterial agent to tackle bacterial infection problems.
Assuntos
Complexos de Coordenação , Infecções por Bactérias Gram-Positivas , Rutênio , Animais , Humanos , Camundongos , Staphylococcus aureus , Rutênio/farmacologia , Rutênio/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Antibacterianos/farmacologia , Antibacterianos/química , Bactérias , Testes de Sensibilidade Microbiana , Cumarínicos/farmacologiaRESUMO
Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC50 values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kß/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.