Multifunctional derivatives of metronidazole

doi:10.1016/S0014-827X(97)00007-4

Il Farmaco

Volume 53, Issue 1, January 1998, Pages 58-61

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Abstract

The design and synthesis of a series of multifunctional metronidazole derivatives are described. The main series are multi-esters having two or more metronidazole groups linked together by aryl or alkyl systems. A second system is two nitro-2-methylimidazole groups joined by a dimethylene link. The third is polymeric 2-(2-methyl-5-nitroimidazol-1-yl)ethyl acrylate. The triester, metronidazole trimesate, is exceptionally active as an antibacterial compound, which appears to be associated with a rigid, three-point attachment.

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1-Methyl-5-nitroimidazolium chloride
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The title salt, C₄H₆N₃O₂⁺·Cl⁻, exhibits multiple hydrogen-bonding interactions involving the nitroimidazolium cation and the chloride anion. Strong hydrogen bonds between the amine hydrogen atom and the chloride anion link the ionic moieties. Of note, with respect to H⋯Cl interactions, the central aromatic hydrogen atom displays a shorter interaction than the other aromatic hydrogen atom. Finally, interactions are observed between the nitro moiety and methyl H atoms. While no π–π stacking is observed, anion-π interactions are present. The crystal was refined as a two-component twin.
Metronidazole within phosphatidylcholine lipid membranes: New insights to improve the design of imidazole derivatives
2018, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
Our results show that substituents of the side chain of metronidazole are important for its interaction with phosphatidylcholine lipid membranes and, consequently, for the disturbance of the membrane. Several studies have been trying to develop new imidazole derivatives (e.g., [66–68]). Ultimately, the structure–toxicity relationship of metronidazole within phosphatidylcholine membranes can provide new insights for the modification and design of new imidazole derivatives with lower toxicity.
Metronidazole is a imidazole derivative with antibacterial and antiprotozoal activity. Despite its therapeutic efficacy, several studies have been developing new imidazole derivatives with lower toxicity. Considering that drug-membrane interactions are key factors for drugs pharmacokinetic and pharmacodynamic properties, the aim of this work is to provide new insights into the structure–toxicity relationship of metronidazole within phosphatidylcholine membranes. For that purpose, lipid membrane models (liposomes and monolayers) composed of dipalmitoylphosphatidylcholine were used. Experimental techniques (determination of partition coefficients and Langmuir isotherm measurements) were combined with molecular dynamics simulations. Different pHs and lipid phases were evaluated to enable a better extrapolation for in vivo conditions. The partition of metronidazole depends on the pH and on the biphasic system (octanol/water or DPPC/water system). At pH 1.2, metronidazole is hydrophilic. At pH 7.4, metronidazole disturbs the order and the packing of phospholipids. For this toxic effect, the hydroxyl group of the side chain of metronidazole is crucial by interacting with the water embedded in the membrane and with the phosphate group and the apolar chains of phospholipids.
PEG-metronidazole conjugates: Synthesis, in vitro and in vivo properties
2005, Farmaco
Citation Excerpt :
Sterile solutions for infusion of 100.0 ml of 5 mg/ml of MTZ solutions are available. Several ester prodrugs of MTZ were reported in an effort to enhance its water solubility for parental administration, chemical stability, and membrane permeability and to diminish the susceptibility to enzymatic degradation [6–10]. In our research, a prodrug approach based on PEG as carrier polymer was adopted to overcome the solubility problem that prevents an easy formulation of parental solution and to modify the pharmacokinetic of the drug.
Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.
2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-fluorobenzoate
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Regular paperMultifunctional derivatives of metronidazole

Abstract

Drug Design

J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Metronidazole: its past, present and future

J. Antimicrob. Chemother.

Nitroimidazoles

Arzneium.-Forsch.

Prodrugs. Part 2. Acylbenzoate esters of metronidazole

Eur. J. Med. Chem.

Crotyl diazoacetate

Org. Syn. Coll.

Regular paper
Multifunctional derivatives of metronidazole