Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines.

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 clickable building blocks remain exceedingly challenging. Herein, we describe a double-click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur-fluoride exchange) process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO2F) and N-acylsulfamides (RCONHSO2NR'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 compounds 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.

Ruthenium polypyridine complexes containing prenyl groups as antibacterial agents against Staphylococcus aureus through a membrane-disruption mechanism.

Four new ruthenium polypyridyl complexes with prenyl groups, [Ru(bpy)2 (MHIP)](PF6 )2 (Ru(II)-1), [Ru(dtb)2 (MHIP)](PF6 )2 (Ru(II)-2), [Ru(dmb)2 (MHIP)](PF6 )2 (Ru(II)-3), and [Ru(dmob)2 (MHIP)](PF6 )2 (Ru(II)-4) (bpy = 2,2'-bipyridine, dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, dmob = 4,4'-dimethoxy-2,2'-bipyridine, and MHIP = 2-(2,6-dimethylhepta-1,5-dien-1-yl)-1H-imidazo[4,f][1,10]phenanthroline), were synthesized and characterized. Their antibacterial activities against Staphylococcus aureus were assessed, and the minimum inhibition concentration (MIC) value of Ru(II)-2 against S. aureus was only 0.5 µg/mL, showing the best antibacterial activity among them. S. aureus could be quickly killed by Ru(II)-2 in 30 min and Ru(II)-2 displayed an obvious inhibitive effect on the formation of a biofilm, which was essential to avoid the development of drug-resistance. Meanwhile, Ru(II)-2 exhibited a stable MIC value against antibiotic-resistant bacteria. The antibacterial mechanism of Ru(II)-2 was probably related to depolarization of the cell membrane, and a change of permeability was associated with the formation of reactive oxygen species, leading to leakage of nucleic acid and bacterial death. Furthermore, Ru(II)-2 hardly showed toxicity to mammalian cells and the Galleria mellonella worm. Finally, murine infection studies also illustrated that Ru(II)-2 was highly effective against S. aureus in vivo.

Silver-mediated radical oxytrifluoromethylation of unsaturated carboxylic acids for the synthesis of γ-trifluoromethylthio lactones.

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.

Copper-catalyzed ortho-selective direct sulfenylation of N-aryl-7-azaindoles with disulfides.

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.

Antibacterial activity of ruthenium polypyridyl complexes against Staphylococcus aureus and biofilms.

There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(bpy)2(ETPIP)](ClO4)2 (Ru(II)-2) and [Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-3) (N-N = bpy = 2,2'-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.

Ancient events and climate adaptive capacity shaped distinct chloroplast genetic structure in the oak lineages.

BACKGROUND: Understanding the origin of genetic variation is the key to predict how species will respond to future climate change. The genus Quercus is a species-rich and ecologically diverse woody genus that dominates a wide range of forests and woodland communities of the Northern Hemisphere. Quercus thus offers a unique opportunity to investigate how adaptation to environmental changes has shaped the spatial genetic structure of closely related lineages. Furthermore, Quercus provides a deep insight into how tree species will respond to future climate change. This study investigated whether closely related Quercus lineages have similar spatial genetic structures and moreover, what roles have their geographic distribution, ecological tolerance, and historical environmental changes played in the similar or distinct genetic structures. RESULTS: Despite their close relationships, the three main oak lineages (Quercus sections Cyclobalanopsis, Ilex, and Quercus) have different spatial genetic patterns and occupy different climatic niches. The lowest level and most homogeneous pattern of genetic diversity was found in section Cyclobalanopsis, which is restricted to warm and humid climates. The highest genetic diversity and strongest geographic genetic structure were found in section Ilex, which is due to their long-term isolation and strong local adaptation. The widespread section Quercus is distributed across the most heterogeneous range of environments; however, it exhibited moderate haplotype diversity. This is likely due to regional extinction during Quaternary climatic fluctuation in Europe and North America. CONCLUSIONS: Genetic variations of sections Ilex and Quercus were significantly predicted by geographic and climate variations, while those of section Cyclobalanopsis were poorly predictable by geographic or climatic diversity. Apart from the different historical environmental changes experienced by different sections, variation of their ecological or climatic tolerances and physiological traits induced varying responses to similar environment changes, resulting in distinct spatial genetic patterns.

Construction of Sulfonyl Phthalides via Copper-Catalyzed Oxysulfonylation of 2-Vinylbenzoic Acids with Sodium Sulfinates.

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.

Morphological and photosynthetic response to high and low irradiance of Aeschynanthus longicaulis.

Aeschynanthus longicaulis plants are understory plants in the forest, adapting to low light conditions in their native habitats. To observe the effects of the high irradiance on growth and physiology, plants were grown under two different light levels, PPFD 650 µmol·m(-2) ·s(-1) and 150 µmol·m(-2) ·s(-1) for 6 months. Plants under high irradiance had significantly thicker leaves with smaller leaf area, length, width, and perimeter compared to the plants grown under low irradiance. Under high irradiance, the leaf color turned yellowish and the total chlorophyll decreased from 5.081 mg·dm(-2) to 3.367 mg·dm(-2). The anthocyanin content of high irradiance leaves was double that of those under low irradiance. The plants under high irradiance had significantly lower Amax (5.69 µmol·m(-2) ·s(-1)) and LSP (367 µmol·m(-2) ·s(-1)) and higher LCP (21.9 µmol·m(-2) ·s(-1)). The chlorophyll fluorescence parameter F v /F m was significantly lower and NPQ was significantly higher in high irradiance plants. RLCs showed significantly lower ETRmax and E k in plants under high irradiance. It can be concluded that the maximum PPFD of 650 µmol·m(-2) ·s(-1) led to significant light stress and photoinhibition of A. longicaulis.

Design, synthesis, anti-infective potency and mechanism study of novel Ru-based complexes containing substituted adamantane as antibacterial agents.

Infections caused by Staphylococcus aureus (S. aureus) are increasing difficult to treat because this pathogen is easily resistant to antibiotics. However, the development of novel antibacterial agents with high antimicrobial activity and low frequency of resistance remains a huge challenge. Here, building on the coupling strategy, an adamantane moiety was linked to the membrane-active Ru-based structure and then developed three novel metalloantibiotics: [Ru(bpy)2(L)](PF6)2 (Ru1) (bpy = 2,2-bipyridine, L = amantadine modified ligand), [Ru(dmb)2(L)](PF6)2 (Ru2) (dmb = 4,4'-dimethyl-2,2'-bipyridine) and [Ru(dpa)2(L)](PF6)2 (Ru3), (dpa = 2,2'-dipyridylamine). Notably, complex Ru1 was identified to be the best candidate agent, showing greater efficacy against S. aureus than most of clinical antibiotics and low resistance frequencies. Mechanism studies demonstrated that Ru1 could not only increase the permeability of bacterial cell membrane and then caused the leakage of bacterial contents, but also promoted the production of reactive oxygen species (ROS) in bacteria. Importantly, complex Ru1 inhibited the biofilm formation, exotoxin secretion and increased the potency of some clinical used antibiotics. In addition, Ru1 showed low toxic in vivo and excellent anti-infective efficacy in two animal infection model. Thus, Ru-based metalloantibiotic bearing adamantane moiety are promising antibacterial agents, providing a certain research basis for the future antibiotics research.

Discovery of quaternized pyridine-thiazole-ruthenium complexes as potent anti-Staphylococcus aureus agents.

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.

Polypyridyl ruthenium complexes with benzothiazole moiety as membrane disruptors and anti-resistance agents for Staphylococcus aureus.

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.

AIE-based ruthenium complexes as photosensitizers for specifically photo-inactivate gram-positive bacteria.

The emergence of multidrug-resistant bacterial have caused severe burden for public health. Particularly, Staphylococcus aureus as one of ESKAPE pathogens have induced various infectious diseases and resulted in increasing deaths. Developing new antibacterial agents is still urgent and challenging. Fortunately, in this study, based on aggregation-induced emission (AIE) ruthenium complexes were designed and synthesized, which realized the high efficiency of reactive oxygen species generation and remarkably killed S. aureus unlike conventional antibiotics action. Significantly, owing to good singlet oxygen production ability, Ru1 at only 4 µg/mL of concentration displayed good antibacterial photodynamic therapy effect upon white light irradiation and could deplete essential coenzyme NADH to disrupt intracellular redox balance. Also, the electrostatic interaction between Ru1 and bacteria enhanced the possibility of antibacterial. Under light irradiation, Ru1 could efficiently inhibit the biofilm growth and avoid the development of drug-resistant. Furthermore, Ru1 possessed excellent biocompatibility and displayed remarkable therapy effect in treating mice-wound infections in vivo. These findings indicated that AIE-based ruthenium complexes as new antibacterial agent had great potential in photodynamic therapy of bacteria and addressing the drug-resistance crisis.

Metal-ruthenium complex based on dipyridylamine group as membrane-active antibacterial agent effectively decrease the development of drug-resistance on Staphylococcus aureus.

Staphylococcus aureus (S. aureus), one of the Gram-positive bacteria, is easily to develop drug-resistance. Drug-resistant S. aureus infection leads to high morbidity and mortality. The complexes, namely [Ru(dpa)2(PSPIP)](PF6)2 (Ru1), [Ru(dpa)2(TSPIP)](PF6)2 (Ru2), and [Ru(dpa)2(TBPIP)](PF6)2 (Ru3), were synthesized using 2, 2'-dipyridylamine as an auxiliary ligand and three main ligands PSPIP, TSPIP, TBPIP. In vitro studies demonstrated that the Ru1-3 exhibited excellent antibacterial activity against S. aureus while showing low hemolytic toxicity to rabbit red blood cells. Notably, Ru3 was found to disrupt the bacterial cell membrane and alter its permeability through fluorescence staining and scanning electron microscopy (SEM) analysis. Furthermore, Ru3 displayed low toxicity in G. mellonella Larvae. Ru3 exhibited good activity against S. aureus in G. mellonella Larvae infection model and mouse skin infection model.To some extent, Ru3 inhibited biofilm formation on S. aureus as well as hemolytic toxin production, thereby attenuating the development of drug resistance without cross-resistance with other antibiotics. In addition, complex Ru3 exhibited a synergistic effect when combined with antibiotics amikacin, kanamycin, tobramycin and chloramphenicol, making it a valuable antibiotics adjuvant.

Coupling a Virulence-Targeting Moiety with Ru-Based AMP Mimics Efficiently Improved Its Anti-Infective Potency and Therapeutic Index.

The surge of antibiotic resistance in Staphylococcus aureus calls for novel drugs that attack new targets. Developing antimicrobial peptides (AMPs) or antivirulence agents (AvAs) is a promising strategy to tackle this challenge. However, AMPs, which kill bacteria by disrupting cell membranes, suffer from low stability and high synthesis cost, while AvAs, which inhibit toxin secretion, have relatively poor bactericidal activity. Here, to address their respective shortcomings, we combined these two different antibacterial activities on the same molecular scaffold and developed a Ru-based metalloantibiotic, termed Ru1. Notably, Ru1 exerted remarkable bactericidal activity (MICS = 460 nM) and attenuated bacterial virulence as well. Mechanistic studies demonstrated that Ru1 had two independent targets: CcpA and bacterial membrane integrity. Based on its dual mechanism of action, Ru1 effectively overcame S. aureus resistance and showed high efficacy in a mouse infection model against S. aureus. This study provides a promising approach to confronting bacterial infections.

Multi-target antibacterial mechanism of ruthenium polypyridine complexes with anthraquinone groups against Staphylococcus aureus.

Three new Ru(ii) complexes, [Ru(dtb)2PPAD](PF6)2 (Ru-1), [Ru(dmob)2PPAD](PF6)2 (Ru-2) and [Ru(bpy)2PPAD](PF6)2 (Ru-3) (dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, dmob = 4,4'-dimethyl-2,2'-bipyridine, bpy = 2,2'-bipyridine and PPAD = 2-(pyridine-3-yl)-1H-imidazo[4,5f][1.10]phenanthracene-9,10-dione), were synthesized and characterized by 1H NMR and 13C NMR spectroscopy, HRMS and HPLC. Among them, Ru-1 showed excellent antimicrobial activity against Gram-positive bacteria Staphylococcus aureus (minimum inhibitory concentration (MIC) = 1 µg mL-1) and low hemolytic and cytotoxic activity. In addition, Ru-1 showed obviously rapid bactericidal activity, low resistance rate, bacterial biofilm destroying activity and high biosafety in vivo. Moreover, skin infection models and a mouse model of sepsis indicated that the anti-infective efficacy of Ru-1 was comparable to that of vancomycin. Mechanism exploration results showed that the antibacterial behavior is probably related with targeting of the bacterial cell membrane and inhibiting topoisomerase I.

Synthesis and biological evaluation of ruthenium complexes containing phenylseleny against Gram-positive bacterial infection by damage membrane integrity and avoid drug-resistance.

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.

Synthesis and biological evaluation of ruthenium complexes bearing the 1,2,4-triazole group as potential membrane-targeting antibacterial agents towards Staphylococcus aureus.

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.

Coumarin-modified ruthenium complexes by disrupting bacterial membrane to combat Gram-positive bacterial infection.

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.

Ruthenium polypyridine complexes with triphenylamine groups as antibacterial agents against Staphylococcus aureus with membrane-disruptive mechanism.

Due to the emergence and wide spread of methicillin-resistant Staphylococcus aureus, the treatment of this kind of infection becomes more and more difficult. To solve the problem of drug resistance, it is urgent to develop new antibiotics to avoid the most serious situation of no drug available. Three new Ru complexes [Ru (dmob)2PMA] (PF6)2 (Ru-1) [Ru (bpy)2PMA] (PF6)2 (Ru-2) and [Ru (dmb)2PMA] (PF6)2 (Ru-3) (dmob = 4,4'-dimethoxy-2,2'-bipyridine, bpy = 2,2'-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine and PMA = N-(4-(1H-imidazo [4,5-f] [1,10] phenanthrolin-2-yl) -4-methyl-N-(p-tolyl) aniline) were synthesized and characterized by 1H NMR, 13C NMR and HRMS. The detailed molecular structure of Ru-3 was determined by single crystal X-ray diffraction. Their antibacterial activities against Staphylococcus aureus (Staphylococcus aureus) were obvious and Ru-3 showed the best antibacterial effect with the minimum inhibitory concentration value of 4 µg ml-1. Therefore, further study on its biological activity showed that Ru-3 can effectively inhibit the formation of biofilm and destroy cell membrane. In vitro hemolysis test showed that Ru-3 has almost negligible cytotoxicity to mammalian red blood cells. In the toxicity test of wax moth insect model, Ru-3 exhibited low toxicity in vivo. These results, combined with histopathological studies, strongly suggest that Ru-3 was almost non-toxic. In addition, the synergistic effect of Ru-3 with common antibiotics such as ampicillin, chloramphenicol, tetracycline, kanamycin and gentamicin on Staphylococcus aureus was detected by chessboard method. Finally, in vivo results revealed that Ru-3 could obviously promote the wound healing of Staphylococcus aureus infected mice.

Synthesis and biological evaluation of ruthenium polypyridine complexes with 18ß-glycyrrhetinic acid as antibacterial agents against Staphylococcus aureus.

Four new ruthenium(II) polypyridine complexes bearing 18ß-glycyrrhetinic acid derivatives, [Ru(bpy)2L](PF6)2 (Ru1), [Ru(dmb)2L](PF6)2 (Ru2), [Ru(dtb)2L](PF6)2 (Ru3) and [Ru(phen)2L](PF6)2 (Ru4) (bpy = 2,2-bipyridine, dmb = 4,4'-dimethyl-2,2'-bipyridine, dtb = 4,4'-di-tert-butyl-2,2'-bipyridine, phen = 1,10-phenanthroline and L is the GA modified new ligand) were designed and synthesized. Their antimicrobial activities against Staphylococcus aureus (S. aureus) were evaluated and all complexes showed an obvious inhibitory effect, especially, the minimum inhibitory concentration (MIC) value of Ru2 was 3.9 µg mL-1. Moreover, Ru2 was found to significantly inhibit the formation of biofilms. The membrane-compromising action mode was suggested to be their potential antibactericidal mechanism. In hemolysis experiments, Ru2 hardly showed cytotoxicity to mammalian erythrocytes. Furthermore, the synergism between Ru2 and common antibiotics, such as ampicillin, chloramphenicol, tetracyclines and ofloxacin, against S. aureus was also detected using the checkerboard method. Finally, a mouse skin infection model was established to evaluate the antibacterial activity of Ru2in vivo, and the results showed that Ru2 could effectively promote wound healing in mice infected with S. aureus. Moreover, the results of histopathological research were consistent with the results of the hemolysis test, indicating that the Ru2 complex was almost non-toxic. Thus, it was demonstrated that the polypyridine ruthenium complexes modified with glycyrrhetinic acid (GA) are a promising strategy for developing interesting antibacterial agents.