Interaction of metronidazole with escherichia coli deoxyribonucleic acid

Malliaros, David P.; Goldman, Peter

doi:10.1016/0006-2952(91)90510-c

Cited by 3 publications

(2 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…66-1.73 (m, 2 H, H-3); 13C NMR (CDCla) 173.2 (C02), 140.5 (C-2'), 128.3 (C-5')*, 125.9 (C-4')*, 51.6 (OCH3), 49.8 (C-5), 33.0 (C-4), 29.7 (C-3), 21.5 (C-2). Hydrolysis as above gave 5-(2-nitroimidazol-lii-yl)pentanoic acid (38), mp (water) 125-126.5 °C.…”

Section: -(Lü-imidazolyl)ethylamine Dihydrochloride (2v2hc1)mentioning

confidence: 97%

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers

Hay

Wilson²,

Moselen³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

A series of novel bis(nitroimidazolyl)alkanecarboxamides has been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitisation in vitro and in vivo. The compounds were prepared by direct coupling of preformed side chain acid and amine components, using diethyl phosphorocyanidate at room temperature. Although designed to be bis-bioreductive prodrugs of DNA cross-linking agents, none of the compounds showed evidence of DNA cross-linking activity, being equally potent against cell lines deficient and proficient in repair of cross-links. However, one of these compounds, N-[2-(2-methyl-5-nitro-1H-imidazolyl)ethyl]-4-(2-nitro-1H- imidazolyl)butanamide (10; SN 24699), showed high hypoxic selectivity as a cytotoxin (rising to 200-fold after exposure to the drug for several hours) in the repair-proficient Chinese hamster cell line AA8. This selectivity was greater than observed for the alkylating 2-nitroimidazole (4; RB 6145) (40-fold) or simple mononitroimidazoles (5-25-fold). Investigation of structure-activity relationships for hypoxic selectivity of bis(nitroimidazoles) was restricted by their low aqueous solubility, but a certain minimum separation of the two nitroimidazole units (by more than five atoms) appears desirable. All the compounds radiosensitized hypoxic cells in vitro but were little more potent as radiosensitizers than the corresponding monomeric nitroimidazoles. Compound 10 caused additional cell killing in the KHT tumor when multiple drug doses were administered in combination with a single dose of radiation. It is not yet clear whether this activity reflects hypoxic cell radiosensitization or cytotoxicity toward hypoxic cells, but this new class of bis-bioreductive agent clearly warrants further investigation.

show abstract

Section: -(Lü-imidazolyl)ethylamine Dihydrochloride (2v2hc1)mentioning

confidence: 97%

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers

Hay

Wilson²,

Moselen³

et al. 1994

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…A suspension of 32 (2.0 g, 6.4 mmol), 3-nitro-l,2,4-triazole (0.81 g, 7.1 mmol), and K2C03 (0.93 g, 6.7 mmol) in DMF (50 mL) was heated at 110 °C for 4 h. The solvent was removed under reduced pressure and the residue chromatographed, eluting with a gradient (0-10%) of MeOH/EtOAc, to give Ñ- NMR [(CD3)2SO] ó 8.83 (s, 1 , H-5'), 8.04 (s, 1 H, H-4'"), 7.50 (t, J = 6. 3 Hz, 1 H, S02NH), 4.42 (t, J = 7.0 Hz, 2 , H-3), 4.33 (t, J = 5.9 Hz, 2 H, H-2"), 3.31 (t, J = 6.2 Hz, 2 H, H-l"), 3.06-3.10 (m, 2 , H-l), 2.47 (s, 3 H, CH3), 2.14-2.22 (m, 2 H, H-2); 13C NMR 162.1 (C-3'), 151.6 (C-2'"), 146.8 (C-5'), 138.3 (C-5'"), 133.1 (C-4'"), 48.6 (C-2"), 47.8 (C-3), 46.4 (C-l"), 41.5 (C-l), 23.5 (C-2), 14.1 (CH3). Anal.…”

Section: (Ch3)mentioning

confidence: 99%

Hypoxia-Selective Antitumor Agents. 10. Bis(nitroimidazoles) and Related Bis(nitroheterocycles): Development of Derivatives with Higher Rates of Metabolic Activation under Hypoxia and Improved Aqueous Solubility

Hay

Lee²,

Wilson³

et al. 1995

J. Med. Chem.

View full text Add to dashboard Cite

A series of analogues of the previously described compound N-[2-(2-methyl-5-nitroimidazol-1H-yl)ethyl]-4-(2-nitroimidazol- 1H-yl)butanamide (4), a novel hypoxic cell cytotoxin and radiosensitizer, have been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitization in vitro. The new derivatives were designed to overcome the low aqueous solubility of 4 and its slow kinetics of killing under hypoxia. The nitroheterocycle unit had a significant effect on solubility, with 3-nitrotriazoles being about 6-fold more soluble than the corresponding 2-nitroimidazoles. Analogues with a range of neutral linker chains (polyhydroxy, alkanesulfonamide, and bisamide) showed only slightly improved solubility and were unable to be fully evaluated. However, a series of analogues with cationic amine linkers had adequate aqueous solubility (up to 280 mM). The amine analogues could not be prepared by direct reduction of precursor amides such as 4 and were most conveniently synthesized by aza-Wittig condensation of the appropriate azide and aldehyde components. The amine-linked compounds were more cytotoxic than 4, with the symmetrical bis(2-nitroimidazole) derivatives (13 and 14) up to 9-fold more potent. They showed hypoxic selectivities comparable to that of 4 (ca. 200-fold) but had much more rapid kinetics of killing under hypoxia, resulting in high hypoxic selectivity at early times in culture. The nature of the mechanism of cytotoxicity of these compounds remains unclear but appears not to be DNA cross-linking, with the compounds showing a lack of hypersensitivity toward repair-deficient UV4 cells. The enhanced solubility and hypoxia-selective cytotoxicity (at early times) of 13 compared with 4 represent significant potential advantages.

show abstract

Metronidazole: an update on metabolism, structure–cytotoxicity and resistance mechanisms

Dingsdag

Hunter

2017

Journal of Antimicrobial Chemotherapy

284

189

View full text Add to dashboard Cite

Metronidazole, a nitroimidazole, remains a front-line choice for treatment of infections related to inflammatory disorders of the gastrointestinal tract including colitis linked to Clostridium difficile. Despite >60 years of research, the metabolism of metronidazole and associated cytotoxicity is not definitively characterized. Nitroimidazoles are prodrugs that are reductively activated (the nitro group is reduced) under low oxygen tension, leading to imidazole fragmentation and cytotoxicity. It remains unclear if nitroimidazole reduction (activation) contributes to the cytotoxicity profile, or whether subsequent fragmentation of the imidazole ring and formed metabolites alone mediate cytotoxicity. A molecular mechanism underpinning high level (>256 mg/L) bacterial resistance to metronidazole also remains elusive. Considering the widespread use of metronidazole and other nitroimidazoles, this review was undertaken to emphasize the structure-cytotoxicity profile of the numerous metabolites of metronidazole in human and murine models and to examine conflicting reports regarding metabolite-DNA interactions. An alternative hypothesis, that DNA synthesis and repair of existing DNA is indirectly inhibited by metronidazole is proposed. Prokaryotic metabolism of metronidazole is detailed to discuss new resistance mechanisms. Additionally, the review contextualizes the history and current use of metronidazole, rates of metronidazole resistance including metronidazole MDR as well as the biosynthesis of azomycin, the natural precursor of metronidazole. Changes in the gastrointestinal microbiome and the host after metronidazole administration are also reviewed. Finally, novel nitroimidazoles and new antibiotic strategies are discussed.

show abstract

Interaction of metronidazole with escherichia coli deoxyribonucleic acid

Cited by 3 publications

References 27 publications

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers

Hypoxia-selective antitumor agents. 8. Bis(nitroimidazolyl)alkanecarboxamides: a new class of hypoxia-selective cytotoxins and hypoxic cell radiosensitizers

Hypoxia-Selective Antitumor Agents. 10. Bis(nitroimidazoles) and Related Bis(nitroheterocycles): Development of Derivatives with Higher Rates of Metabolic Activation under Hypoxia and Improved Aqueous Solubility

Metronidazole: an update on metabolism, structure–cytotoxicity and resistance mechanisms

Contact Info

Product

Resources

About