Synthesis and antibacterial activity of 1-hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide and related compounds

Since 1940s, Quinoxaline 1,4-dioxides (QdNO's) are known as potent antibacterial agents, and subtherapeutic levels have been used to promote growth and improve efficiency of feed conversion in animal feed. They have also shown a selective cytotoxicity against hypoxic cells present in solid tumours. Furthermore, recent studies have put in evidence that QdNO's are endowed with antitubercular, antiprotozoal and anticandida activities. On the other hand, several authors have reported about photoallergic and mutagenic effects of some derivatives. QdNO's may also cause the development of antibiotic-resistant bacteria and influence the horizontal transfer of virulence genes between bacteria. In this review article we report the biological properties, the mode of action and Structure Activity Relationship (SAR) studies of the QdNO derivatives. Furthermore, some cytogenetic and genotoxic effects, classical and more recent method of synthesis, the quinoxaline 1,4-dioxides, and some of their most important reactions, were also reported.

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“…to the quinoxaline 1,4-dioxides, is well-documented [88,132,[147][148][149][150][172][173][174][175][176]. Some examples are showed in Fig.…”

Section: ) Cyclization and Cycloaddition Reactionsmentioning

confidence: 99%

Quinoxaline 1,4-Dioxide: A Versatile Scaffold Endowed With Manifold Activities

Carta

Corona²,

Loriga

2005

CMC

136

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“…mental in vivo models [3,4,1]. In the past few years, several quinoxaline 1,4-di-N-oxides have been described which present in vitro antituberculous activity against Mycobacterium tuberculosis H37Rv and also against clinical cultures of Mycobacterium tuberculosis [5][6][7][8][9][10].…”

Section: Antibiotics • Antiviral Drugs • Chemotherapeutics • Cytostaticsmentioning

confidence: 99%

Comparative Acute Systemic Toxicity of Several Quinoxaline 1,4-Di-N-oxides in Wistar Rats

Azqueta

Gil

García‐Rodríguez

et al. 2011

Arzneimittelforschung

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The acute toxicity of six quinoxaline 1,4-di-N-oxides has been evaluated in an attempt to determine: a) the feasibility of testing systemic toxicity of these compounds in a very preliminary phase without an adequate formulation for in vivo administration, b) the LD50 range and the toxic target organ of these compounds in order to have an approximation of the structure-activity relationship. Quinoxaline 1,4-di-N-oxides have shown a great variety of biological activities with potential therapeutic application in cancer, malaria, etc. Problems of toxicity hinder the progression of these compounds to clinical phases. The compounds dissolved in DMSO at their solubility limit were administered i.v. to female Wistar rats (8 weeks, 160 g), using an infusion pump (300 microL; 20 microl/min). Animals were observed for a period of 14 days. This dose of the vehicle (1.7 ml/kg) was well tolerated by the animals. The LD50 could not be determined, but a marked hypoactivity was induced by the treatment. The same compounds were also injected intraperitoneally, suspended in 0.01% Tween 80/0.09 % saline, and the animals that did not die were observed for a period of 14 days. The LD50 could be estimated to be in a range between 30 and 120 mg/kg, except for one of the compounds. A decrease in the evolution of body weight and hypoactivity were the principal symptoms induced by the treatment. In both assays, histopathologic study of heart, liver, kidney, lung, spleen and ovaries indicated that the target organs may be heart and spleen. In conclusion, the i.v. route is not adequate for estimating the LD50 of these compounds due to solubility problems; by i.p. route, the LD50 interval is between 30 and 120 mg/kg. The data did not permit the deduction of any specific structure-activity relationship.

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“…The 13C and XHNMRspectra, including 13C distortionless enhancement by polarization transfer (DEPT), XH homonuclear correlation spectroscopy (COSY) and 1H-13C heteronuclear correlation spectroscopy (HETCOR)experiments, of CP-78,545 Mg-salt were most informative, and Table 2 gives the complete chemical shift assignments. Since the Mg-salt of zincophorin has not been reported, our spectra were instead compared with those for the Mg-salt of griseochelin (5), which was knownto be closely related to or identical with zincophorin. Griseochelin has the same gross structure as zincophorin, however, an X-ray structure has not been determined for griseochelin and the Only the olefinic region is shown.…”

Section: Structural Determinationmentioning

confidence: 99%

“…Indeed, a remarkable similarity between CP-78,545 Mg-salt (2) and griseochelin Mg-salt (5) was noted as regards to :H and 13C NMRdata, with the exception of the chemical shifts for C-23, C-24 and C-25, and the protons that are attached to these carbons ( Table 2). Some assignments for 2 were made by analogy with the chemical shifts and assignments for griseochelin Mg-salt (5), since a detailed NMRanalysis had already been performed for this compound2). The following 13C connectivities for 2 were assumed: C 4 The structure and relative stereochemistry of 3 was determined by X-ray crystallography using a crystal which measured 0.32 x0.10x0.08 mm.Diffraction measurements were madeon an Enraf-Nonius CAD-4fully automated diffractometer using graphite monochromated CuKaradiation (X = 1.54184 A).…”

Section: Structural Determinationmentioning

confidence: 99%

CP-78,545, a new monocarboxylic acid ionophore antibiotic related to zincophorin and produced by a streptomyces.

et al. 1989

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Anew monocarboxylic acid ionophore antibiotic related to zincophorin, CP-78,545 (1). was found in the culture broth of Streptomyces sp. N731-45. CP-78,545 was extracted with organic solvents and purified by column chromatography. The metabolite, which is active in vitro against certain Gram-positive bacteria, as well as the anaerobe Treponema hyodysenteriae, and a coccidium Eimeria tenella, was isolated as a water insoluble magnesiumsalt (2) in 2 : 1 (ligand/metal) stoichiometry. The structure of CP-78,545 was elucidated by spectroscopic (NMRand MS) methods, and the relative stereochemistry was determined by single-crystal X-ray analysis of the cadmium salt (3). CP-78,545, i.e., 24-dehydrozincophorin, is unique since its molecular backbone contains a terminal double bond previously not found in other polyether ionophores.

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Synthesis and antibacterial activity of 1-hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide and related compounds

Cited by 25 publications

References 1 publication

Quinoxaline 1,4-Dioxide: A Versatile Scaffold Endowed With Manifold Activities

Quinoxaline 1,4-Dioxide: A Versatile Scaffold Endowed With Manifold Activities

Comparative Acute Systemic Toxicity of Several Quinoxaline 1,4-Di-N-oxides in Wistar Rats

CP-78,545, a new monocarboxylic acid ionophore antibiotic related to zincophorin and produced by a streptomyces.

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