Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines

Parhi, Ajit K.; Zhang, Yongzheng; Saionz, Kurt W.; Pradhan, Padmanava; Kaul, Malvika; Trivedi, Kalkal; Pilch, Daniel S.; LaVoie, Edmond J.

doi:10.1016/j.bmcl.2013.06.048

Cited by 144 publications

(60 citation statements)

References 37 publications

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“…General sensitivity testing on a series of hydrazones, revealed 77 to be the most promising with widest zone of inhibition [90]. Bacteriostatic activity of other quinoxaline derivatives 78 [91], 79 [92], 80 [93], 81 [94] and 82 [95] had been reported. Further studies also established that steroidal-based oxazoloquinoxalines 83 [96a] and its thiazolo-counterpart 84 [96b] were better antibacterial agents than the standard drug amoxicillin and chloramphenicol respectively [96].…”

Section: Antibacterial Activitymentioning

confidence: 99%

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

Ajani

2014

European Journal of Medicinal Chemistry

100

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Section: Antibacterial Activitymentioning

confidence: 99%

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

Ajani

2014

European Journal of Medicinal Chemistry

100

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“…Taking this background into account and considering the biologic and antitumor activities of quinazoline derivatives [25][26][27][28][29], the purpose of the present work was to study the cytotoxicity of modified MWCNTs on a human noncancerous cell line (HEK293) and a cancerous one (SKBR3). Our study indicates that MWCNT-quin is highly toxic to cancer cells, and this effect is highly significant compared to its effect on noncancerous cell samples.…”

Section: Statistical Analysesmentioning

confidence: 99%

Synthesis, characterization, and toxicity of multi-walled carbon nanotubes functionalized with 4-hydroxyquinazoline

Tahermansouri¹,

Mirosanloo²,

Keshel³

et al. 2016

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The attachment of 2-aminobenzamide to carboxylated multi-wall carbon nanotubes (MWCNTs)-COOH was achieved through the formation of amide bonds. Then, the functionalized MWCNTs, MWCNT-amide, were treated by phosphoryl chloride to produce MWCNT-quin. The products were characterized by Fourier transform infrared spectroscopy, Raman spectroscopy, scanning electron microscopy, thermogravimetric analysis, derivative thermogravimetric, steady-state fluorescence spectroscopy, and solubility testing. MWCNT-quin showed photo-electronic properties, which is due to the attachment of the 4-hydroxyquinazoline groups to them as proved by steady-state fluorescence spectroscopy. This suggests intramolecular interactions between the tubes and the attached 4-hydroxyquinazoline. The toxicity of the samples was evaluated in human embryonic kidney HEK293 and human breast cancer SKBR3 cell lines, and the viable cell numbers were measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) after the cells were cultured for 24 h. Cellular investigations showed that the modified MWCNTs, particularly MW-CNT-quin, have considerably significant toxic impact on SKBR3 as compared to HEK293 at the concentration of 5 µg/mL.

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“…Its appeal is further supported for several reasons: (i) it is an essential bacterial protein for survival; (ii) it is highly conserved across many bacterial species, making it a potential broad target; (iii) it is not present in eukaryotes, and toxicity therefore would be expected to be low; and (iv) it is a novel target currently unexploited by other therapeutic options and therefore would be expected to present a low probability of cross-resistance with other therapies. Previous in vitro studies have demonstrated that a number of FtsZ inhibitor compounds contain antibacterial potency against Gram-positive pathogens, including isolates with phenotypic resistance to other antibiotics (14,(45)(46)(47)(48)(49)(50)(51).…”

Section: Figmentioning

confidence: 99%

In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

Lepak

Parhi²,

Madison

et al. 2015

Antimicrob Agents Chemother

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Antibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5 Staphylococcus aureus isolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C max ) were relatively linear over the doses studied. Methicillin-resistant Staphylococcal aureus (MRSA) infections are a major public health threat (1). In the United States, S. aureus is the most common cause of nosocomial infection and leads to more than 80 thousand illnesses and 11 thousand deaths yearly (2). Ambulatory visits for cases of skin and soft tissue infection (SSTI) continue to increase in number and amounted to more than 14 million in a 2005 survey (3). Methicillin-resistant S. aureus infections account for a disproportionate rise in the incidence of those cases and in the need for hospitalization and unfortunately have limited therapeutic options (3-6). Novel antimicrobial agents that target cellular functions distinctly different from those targeted by current therapies and that show activity against drug-resistant isolates are urgently needed (7-10). Bacterial cell division represents an attractive area for antibiotic research to meet these needs.FtsZ is a major functional protein involved in cell division through formation of a Z-ring polymeric structure of FtsZ subunits (11-13). Disruption of this process leads to inhibition of cell division and eventual cell death (14). In addition to its novel mechanism of action, FtsZ is an attractive drug target because it is highly conserved in bacteria but absent in eukaryotic cells.We describe a pharmacodynamic (PK) evaluation of a methoxybenzamide FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, in a murine neutropenic thigh infection model against S. aureus. The impact of dose and dosing regimen on the in vivo efficacy of this drug was assessed. Specifically, the studies included were designed to (i) determine the pharmacokinetic/ pharmacodynamic (PK/PD) index (peak serum level divided by the MIC [C max /MIC], area under the concentration-time curve over 24 h in the steady state divided by the MIC [AUC/MIC ratio], or duration of time serum levels exceed the MIC [time above MIC]) associated with optimal drug efficacy and (ii) identify the magnitude of the PK/PD index value required for efficacy among multiple S. aureus isolates, including those with beta-lactam resistance. MATERIALS AND METHODSOrganisms, media, and anti...

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Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines

Cited by 144 publications

References 37 publications

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

Synthesis, characterization, and toxicity of multi-walled carbon nanotubes functionalized with 4-hydroxyquinazoline

In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

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