Wei-Wei Gao

Design, synthesis and biological evaluation of amino organophosphorus imidazoles as a new type of potential antimicrobial agents

A series of amino organophosphorus imidazoles were designed and synthesized as a novel structural type of antimicrobial agents. Bioactive evaluation in vitro showed that compound 3f exhibited equipotent or superior anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) and anti-S. cerevisiae efficiencies (minimal inhibitory concentration (MIC)=2 μg/mL) to clinical drugs, and the combinations with antibacterial or antifungal drugs enhanced the antimicrobial efficiency. Highly active molecule 3f showed low propensity for bacteria to develop resistance, and the preliminary action mechanism studies demonstrated that 3f was membrane-active, but had no significant intercalation towards MRSA DNA. The computational study on 3f reasonably explained its high antimicrobial activity. Experimental data revealed that ground-state 3f-HSA complexes were formed mainly through hydrophobic interactions and hydrogen bonds with a spontaneous process, and the non-radioactive energy transfer from HSA to 3f occurred beyond Förster resonance energy transfer theory. The participation of metal ions in 3f-HSA supramolucular system could increase the concentration of free compound 3f, and shorten its storage time and half-life in the blood to improve the maximum antimicrobial efficacy.

Novel potentially antifungal hybrids of 5-flucytosine and fluconazole: Design, synthesis and bioactive evaluation

A series of novel potentially antifungal hybrids of 5-flucytosine and fluconazole were designed, synthesized and characterized by 1H NMR, 13C NMR, IR and HRMS spectra. Bioactive assay manifested that some prepared compounds showed moderate to good antifungal activities in comparison with fluconazole and 5-flucytosine. Remarkably, the 3,4-dichlorobenzyl hybrid 7h could inhibit the growth of C. albicans ATCC 90023 and clinical resistant strain C. albicans with MIC values of 0.008 and 0.02 mM, respectively. The active molecule 7h could not only rapidly kill C. albicans but also efficiently permeate membrane of C. albicans. Molecular docking study revealed that compound 7h could interact with the active site of CACYP51 through hydrogen bond. Quantum chemical studies were also performed to explain the high antifungal activity. Further preliminary mechanism research suggested that molecule 7h could intercalate into calf thymus DNA to form a steady supramolecular complex, which might block DNA replication to exert the powerful bioactivities.

Discovery of natural berberine-derived nitroimidazoles as potentially multi-targeting agents against drug-resistant Escherichia coli

A series of natural berberine-derived nitroimidazoles as novel antibacterial agents were designed, synthesized and characterized by nuclear magnetic resonance (NMR), infrared spectra (IR), and high resolution mass spectra (HRMS) spectra. The antimicrobial evaluation showed that some target molecules exhibited moderate to good inhibitory activities against the tested bacteria and fungi including clinical drug-resistant strains isolated from infected patients. Especially, 2-fluorobenzyl derivative 8f not only gave strong activity against drug-resistant E. coli with the minimal inhibitory concentration (MIC) value of 0.003 mM, 33-fold more active than norfloxacin, but also exhibited low toxicity toward RAW 264.7 cells and less propensity to trigger resistance. The aqueous solubility and ClogP values of target compounds were investigated to elucidate the structureactivity relationships. Molecular docking and quantum chemical studies for compound 8f rationally explained its antibacterial effect. The further exploration of antibacterial mechanism revealed that the highly active compound 8f could effectively permeabilize E. coli cell membrane and intercalate into DNA isolated from resistant E. coli to form 8f-DNA complex that might block DNA replication to exert the powerful bioactivities. Compound 8f could also selectively address resistant E. coli from a mixture of various strains.

Discovery of Benzimidazole-Quinolone Hybrids as New Cleaving Agents toward Drug-Resistant Pseudomonas aeruginosa DNA

A series of benzimidazole–quinolone hybrids as new potential antimicrobial agents were designed and synthesized. Bioactive assays indicated that some of the prepared compounds exhibited potent antibacterial and antifungal activities. Notably, 2‐fluorobenzyl derivative 5 b (ethyl 7‐chloro‐6‐fluoro‐1‐[[1‐[(2‐fluorophenyl)methyl]benzimidazol‐2‐yl]methyl]‐4‐oxo‐quinoline‐3‐carboxylate) showed remarkable antimicrobial activity against resistant Pseudomonas aeruginosa and Candida tropicalis isolated from infected patients. Active molecule 5 b could not only rapidly kill the tested strains, but also exhibit low toxicity toward Hep‐2 cells. It was more difficult to trigger the development of bacterial resistance of P. aeruginosa against 5 b than that against norfloxacin. Molecular docking demonstrated that 5 b could effectively bind with topoisomerase IV–DNA complexes, and quantum chemical studies theoretically elucidated the good antimicrobial activity of compound 5 b. Preliminary experimental reaction mechanism exploration suggested that derivative 5 b could not intercalate into DNA isolated from drug‐resistant P. aeruginosa, but was able to cleave DNA effectively, which might further block DNA replication to exert powerful bioactivities. In addition, compound 5 b is a promising antibacterial agent with membrane disruption abilities.

Study of a novel phosphorus-containing flame retardant for cotton fabric

In this paper, a high efficiency FR named HPA was applied to treat cotton fabric. The results of LOI values and vertical flammability test showed that HPA treated cotton fabric had the best flame retardancy (LOI value was 36.0%), when the FR concentration is 50 g/L, and cured at 180°C for 7 min. During the process of holding back the combustion, HPA behaves the excellent properties of FR for cotton fabric.

A concise water-solvent synthesis of highly effective, durable, and eco-friendly flame-retardant coating on cotton fabrics

A new halogen-free and formaldehyde-free ammonium salt of melamine hexa(methylphosphonic acid) (AMHMPA) was facilely synthesized as flame retardant (FR) material under water-solvent and low temperature condition to counter inflammable cotton fabric fire hazard. The reactive PO(NH4)2 and PO(OH)2 groups from AMHMPA reacted with cotton reactive OH groups to form POC bonds. A layer of AMHMPA was coated onto the treated-cotton surface, and a carbon skeleton was formed after combustion. The char residue percentages of the treated-cotton fabrics and untreated fabric were 38.5 and 3.6% at 600 °C, respectively. The phosphorus contents for the control, treated-cotton and burned-cotton were 0, 37.499 and 24.896%, respectively. The LOIs of cotton treated with 30-90 g/L AMHMPA reached 32.0-43.0%. After 50 laundering cycles (LCs), the LOIs still maintained 26.0-33.4%. AMHMPA-treated cotton had no cytotoxicity towards the environment and humans. These results demonstrated that AMHMPA-treated cotton exhibited eco-friendly, outstanding durability and excellent flame retardancy. TG-IR and cone calorimeter results confirmed AMHMPA condensation phase flame retardant mechanism.