چكيده به لاتين
first section: Abstract
Synthesis of new β-substituted trimethine oxonol dyes using vinamidinium salts
Oxonol dyes are an important class of polymethine dyes in which two heterocyclic rings containing oxygens are linked by a polymethine chain as shown in Figure 1.
Figure 1. General structure of polymethine oxonol dyes.
Oxonol dyes have unique intrinsic properties such as relatively good stability, high molar absorption coefficients, ability to generate triplet state oxygen and cytotoxic singlet oxygen (1O2) and prominent fluorescence characteristics which led to use of oxonol dyes as fluorescent probes for biological studies and photodynamic therapy agents.
However, very few synthetic procedures are available for oxonol dyes and they present unsubstituted oxonol dyes in polymethine chain along with small Stokes shifts. Therefore, introducing bulky substituents with tailored steric hindrance and resonance effects into the polymethine chain can lead to increasing Stokes shift.
Herein, a mild and efficient 3-step procedure was developed to access novel trimethine oxonol dyes carrying quaternary pyridinium groups at the β position of polymethine chain. The procedure involves a simple triethylamine-promoted condensation of 1,3-dimethylbarbituric acid or 1,3-indandione with preformed vinamidinium salts (scheme 1).
Scheme 1. Synthetic pathway to synthesis of oxonol dyes.
1H NMR, 13C NMR, IR and HR-MS spectral data confirmed the structures of the dyes. Their photophysical properties such as the maximum absorption and fluorescence emission, molar absorption coefficient (), Stokes shift and fluorescence quantum yield f) were measured at room temperature. Density functional theory calculations were carried out on the dyes at the B3LYP/6–311G(d,p) level of theory to investigate the conformational changes arising from the different substituents and identified planar cis or trans configurations.
Keywords: Trimethine oxonol dyes, Vinamidinium salts, Fluorescence, Photodynamic therapy agents.
Second section: Abstract
Synthesis of cephalosporin-3'-diazeniumdiolates (C3Ds) as NO-donor antibiotics
Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings, where they are the primary cause of a wide range of chronic infections. There is an urgent unmet need to discover novel anti-biofilm drugs and therapeutic strategies to improve the treatment or chronic infections and support the reduction of antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that disperse biofilms and render them more susceptible to antibiotics. Biofilm dispersing NO-donor prodrugs hold great promise as new treatments for biofilm-medicated chronic infections. Cephalosporin-3’-diazeniumdiolates (C3Ds) are NO-donor prodrugs that are capable of highly specific and targeted delivery of NO to biofilm infection sites following reaction with bacterial -lactamases. Localization of NO to biofilm infection sites lowers the risk of NO mediated side effects, which would likely be observed with non-targeted NO donor drugs.
With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO by reactions with transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (-lactam-mediated) antibacterial effects. This dual-activity concept provides a novel and potentially superior approach in the therapeutic use of C3Ds Creation of dual-activity C3Ds requires development of new analogs that show increased stability towards -lactamases and high reactivity towards PBPs. High penetration through Gram-negative bacterial cell walls is also required. due to have higher generation of cephalosporin and primary amine in diazeniumdiolates moiety and also release NO following reaction with the bactericidal target of -lactam antibiotics, Penicillin Binding Proteins (PBPs) achieving both biofilm dispersion and bacterial cell death from the same drug.
Scheme 1. Proposed mechanism for release of NO from cephalosporin-3՛-diazeniumdiolates
The aim of this project was synthesis two new classes of C3Ds based on the later generation cephalosporins ceftazidime and cephalexin; i.e. ceftazidime-3'-diazeniumdiolate and cefalexin-3'-diazeniumdiolate. Ceftazidime-3'-diazeniumdiolate (C3D) was designed to show increased stability against enzyme -lactamase and high reactivity towards penicillin-binding proteins (PBPs), leading to biofilm-dispersing NO release and -lactam-mediated bactericidal activity without the need for co-administered antibiotics. Cefalexin-3'-diazeniumdiolate (C3D) could show increases solubility and better penetration through Gram-negative cell walls.
Keywords: Bacterial biofilm, Cephalosporin-3'-diazeniumdiolates (C3Ds), Anti-biofilm drugs, Biofilm dispersing NO-donor agent.
