Abstract:In this paper a new series of chalcogenides of diphenylmethylaminophosphine derived from ciprofloxacin (PPh 2 CH 2 Cp) and a new phosphine derived from norfloxacin (PPh 2 CH 2 Nr) are presented. The synthesized compounds were characterized by NMR, MS and X-ray techniques. Both phosphines exhibit antibacterial activity against: S. aureus, E. coli, K. pneumoniae and P. aeruginosa, similar to ciprofloxacin and norfloxacin. They inhibit the growth of microorganisms in relatively low concentrations. Chalcogenides a… Show more
“…Some have been developed into resistance protein inhibitors, including avibactam, clavulanic acid, tazobactam, and sulbactam 15 16 17 18 . One recent study synthesized phosphine derivatives of ciprofloxacin and norfloxacin, yielding an additional class of broad-spectrum antibiotics effective against P. aeruginosa, S. aureus, K. pneumoniae , and E. coli 19 . Phosphorus-containing functional groups could yield compounds with unique biochemistry, such as stronger binding affinity to certain enzymes as compared to carbon or nitrogen analogs.…”
The acronymously named “ESKAPE” pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to “eskape” antibiotic treatment12. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.
“…Some have been developed into resistance protein inhibitors, including avibactam, clavulanic acid, tazobactam, and sulbactam 15 16 17 18 . One recent study synthesized phosphine derivatives of ciprofloxacin and norfloxacin, yielding an additional class of broad-spectrum antibiotics effective against P. aeruginosa, S. aureus, K. pneumoniae , and E. coli 19 . Phosphorus-containing functional groups could yield compounds with unique biochemistry, such as stronger binding affinity to certain enzymes as compared to carbon or nitrogen analogs.…”
The acronymously named “ESKAPE” pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to “eskape” antibiotic treatment12. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.
“…Chemical shift for KeOP was 27.18, for KeSP was 35.15 and for KeSeP the chemical shift was 25.93 ppm with the 1 J satellite coupling to 77 Se equal to 721.5 Hz. All these values are typical for the diphenylphosphanomethyl ligands with N4-substituted piperazine ring attached to the P atom via methylene group and do not depend on N4 substituent 40,45 . In 1 H and 13 C{ 1 H} NMR spectra, phosphane formation from KedA results in the new signals of methylene group being a link between KedA and -PPh 2 moieties.…”
Section: Resultsmentioning
confidence: 72%
“…Briefly, we added KedA to the solution of PPh 2 CH 2 OH obtained in situ from PPh 2 (CH 2 OH) 2 Cl by adding the excess of NEt 3 . Chalcogenides were synthesized in a reaction of KeP with a stoichiometric amount of H 2 O 2, resublimed sulphur or metallic selenium in the ultrasound bath 34,44,45,48 . To confirm the assumed structures and check the purity of the products we employed mass spectrometry and elemental analysis as well as NMR spectroscopy.Figure 1Molecular schemes of ketoconazole ( Ke ) and its derivatives.…”
Four new derivatives of ketoconazole (Ke) were synthesized: diphenylphosphane (KeP), and phosphane chalcogenides: oxide (KeOP), sulphide (KeSP) and selenide (KeSeP). These compounds proved to be promising antifungal compounds towards Saccharomyces cerevisiae and Candida albicans, especially in synergy with fluconazole. Simulations of docking to the cytochrome P450 14α-demethylase (azoles’ primary molecular target) proved that the new Ke derivatives are capable of inhibiting this enzyme by binding to the active site. Cytotoxicity towards hACSs (human adipose-derived stromal cells) of the individual compounds was studied and the IC50 values were higher than the MIC50 for C. albicans and S. cerevisiae. KeP and KeOP increased the level of the p21 gene transcript but did not change the level of p53 gene transcript, a major regulator of apoptosis, and decreased the mitochondrial membrane potential. Taken together, the results advocate that the new ketoconazole derivatives have a similar mechanism of action and block the lanosterol 14α-demethylase and thus inhibit the production of ergosterol in C. albicans membranes.
“…They showed the potential to induce a programmed cell death by apoptosis with the ability to induce reactive oxygen species and single strand breaks formation in addition to DNA intercalation. Ciprofloxacin 54 and norfloxacin 55 complexes were the most potent ones with IC 50 ranges 2.5–5.9 and 2.4–5.0 µM, respectively, when screened using human A549 and murine colon carcinoma CT26 cell lines . Lomefloxacin was also coordinated with different metal ions Mn(II), Co(II), Ni(II), Cu(II), and Zn(II)) and investigated for the biological activity along with the parent free drug.…”
Section: Fluoroquinolone Metal Ion Complexes With Anticancer Activitymentioning
Different studies about the anticancer potential of several medically used antibacterial fluoroquinolones have been established. Fluoroquinolone derivatives, like some anticancer drugs, such as doxorubicin, can achieve antitumor activity via poisoning of type II human DNA topoisomerases. Interestingly, structural features required for the anticancer activity of quinolones have been determined. Most of the chemical modifications required to convert antibacterially acting fluoroquinolones into their anticancer analogs were at position 7 and the carboxylic group at position 3. This review highlights the antitumor potential of fluoroquinolones in general and summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. Moreover, the review gives a quick recap on metal ion chelates with fluoroquinolones and their substantial role in topoisomerase poisoning and antitumor potential improvement. Hence, it should be highly interesting for researchers attempting to design and synthesize novel anticancer fluoroquinolone candidates. K E Y W O R D S anticancer, DNA topoisomerase, metal ion complexes, quinolones Arch Pharm Chem Life Sci. 2019;352:1800376.wileyonlinelibrary.com/journal/ardp
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