- Metronidazole prodrugs: Synthesis, physicochemical properties, stability, and ex vivo release studies
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The aim of the present study was to develop a colon targeted delivery system for metronidazole using polymeric prodrug formulation. Two chitosan amide conjugates of metronidazole were prepared by using two different spacers to covalently link the drug to the amino group of the chitosan glucosamine units. Glutaric and succinic hemiesters of metronidazole were thus prepared and then coupled to chitosan to obtain metronidazole-glutaryl- and metronidazole- succinyl-chitosan conjugates. Polymeric prodrugs were characterized by solid state NMR method, namely carbon 13 cross polarization magic angle spinning (13C NMR CPMAS). Prodrug stability study was carried out in acid (pH = 1.2) and in alkaline (pH = 7.4) buffers in a thermostatic bath at 37 °C. Drug release from the two prodrugs was studied by incubating each of them with 10% w/v cecal and colonic content of rats. Obtained results showed that both prodrugs were adequately stable in acid environment, while the succinyl conjugate was more stable than the glutaryl one in alkaline buffer. Both the prodrugs released the drug in cecal and colonic content, showing that the two systems could serve as colon specific delivery systems of metronidazole.
- Mura, Carla,Valenti, Donatella,Floris, Costantino,Sanna, Roberta,De Luca, Maria Antonietta,Fadda, Anna Maria,Loy, Giuseppe
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- Synthesis of fluorescent drug molecules for competitive binding assay based on molecularly imprinted polymers
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Fluorescent immunosorbent assay (FIA) is very promising for sensitive and selective analysis in bio-medical applications. Here, we proposed an assay, using fluorescent engineering of analytes and the corresponding molecularly imprinted polymers (MIPs) as a plastic antibody. Three drug molecules (metronidazole, zidovudine and lamivudine) were condensed with 9-aminoacridine, using succinic anhydride as a spacer. The target products were characterized with 1H-NMR, IR and mass spectrometry. UV-vis absorption and fluorescent properties of the fluorophore-labeled drug molecules were investigated. Feasibility of the fluorescent biomimetic immunosorbent assay based on MIPs was demonstrated in the solution. This work will provide sound foundation for the future application in real sample.
- Wubulikasimu, Muyasier,Muhammad, Turghun,Imerhasan, Mukhtar,Hudaberdi, Nurmemet,Yang, Wenwu,Zhao, Jianzhang,Peng, Xiaojun
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- Chicken IgY bifunctional antibody for treating Helicobacter pylori
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The invention provides a chicken IgY bifunctional antibody for treating helicobacter pylori, relates to the field of therapeutic bifunctional antibodies and relates to a chicken IgY antibody for treating helicobacter pylori and a modification method of the chicken IgY antibody. The invention aims at adopting a method of a bifunctional antibody to solve the problems of drug resistance of helicobacter pylori treatment medicines, long treatment period and radical treatment difficulty of an orally-taking IgY antibody and achieves the effect of antibiotic and anti-helicobacter pylori antibody bifunctional helicobacter pylori treatment by modifying a helicobacter pylori resistant chicken IgY antibody with multiple chemical substances and multiple different methods, so that the treatment period can be shortened, the drug resistance of the helicobacter pylori on antibiotics can be reduced, toxic and side effects of antibiotics can be reduced, and the treatment scheme on the helicobacter pylorican be optimized.
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Paragraph 0035-0037
(2020/06/20)
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- Efficient acylation and one-pot synthesis of dehydroandrographolide succinate on a large scale assisted with microwave radiation
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A rapid and convenient method for acylation and large-scale synthesis of dehydroandrographolide succinate has been developed under microwave irradiation. It is a one-pot condensation and is compatible with dehydration and rearrangement of double bond in mild reaction conditions with good yield, high purity (up to 99.8%), time-savings, few pollutants and low cost. In addition, a number of acylation derivatives were synthesized under microwave irradiation.
- Luo, Xin-Feng,He, Ling,Yin, Hai-Bin,Zheng, Hu,Bei, Di,Deng, Jin-Jin,Huang, Wen-Cai
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experimental part
p. 3444 - 3452
(2009/12/05)
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- ANTIBACTERIAL AND/OR ANTIPROTOZOAL NITROIMIDAZOLE DERIVATIVE COMPOUNDS WITH UREASE INHIBITOR ACTIVITY, PROCESS FOR PREPARING THESE COMPOUNDS AND USE IN PHARMACEUTICAL COMPOSITIONS AND MEDICINES.
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The present application describes nitroimidazolic derivative compounds with antibacterial and/or antiprotozoal activity, which are potent urease inhibitors. It also describes the process for preparing those compounds and their use in pharmaceutical compositions and medicines.
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Page/Page column 26
(2008/06/13)
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- Metronidazole twin ester prodrugs II: Non identical twin esters of metronidazole and some antiprotozoal halogenated hydroxyquinoline derivatives
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New non identical twin ester prodrugs 3a-d were synthesized by linking metronidazole and some antiprotozoal halogented 8-hydroxyquinoline derivatives via dicarboxylic acid spacers with the aim of improving the therapeutic efficacy of both drugs. The synthesis necessitates the preparation of the precursor metronidazole hemisuccinate or hemiphthalate followed by estrification with the respective hydroxyquinoline derivative. To assess their suitability as prodrugs, the lipophilic properties, chemical stability as well as in vitro and in vivo enzymatic hydrolysis were investigated. The lipophilic properties, expressed as Rm values were determined using RP-TLC and showing enhanced lipophilicity as compared with the parent drugs. Hydrolysis kinetics of the prepared twin esters at 37°C using HPLC, indicated a quantitative release of the parent drugs in two step reaction (K1 and K2) via formation of metronidazole hemiesters followed by spontaneous hydrolysis of the later to metronidazole. The twin esters were adequately stable in aqueous buffer solutions than in biological media and the second rate (K2) of hydrolysis is more accelerated than the first (K1). Bioavailability study of 1-(5-chloro-7-iodoquinolin-8-yl)-4-[2-(2-methyl-5- nitro-1-H-imidazolyl)ethyl]butandioate, 3a, as well as equivalent amount of the corresponding physical mixture of metronidazole and 5-chloro 7-iodo-8- hydroxyquinoline in rabbits has shown that, the plasma level of the released metronidazole from the prodrug is higher than that resulting from the physical combination. A considerable amount of 5-chloro-7-iodo- hydroxyquinoline was detected in plasma, however, no measurable concentration of the quinoline derivative was observed in rabbit plasma from the physical mixture.
- Aboul-Fadl, Tarek,Mahfouz, Nadia M.
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p. 309 - 324
(2007/10/03)
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- Metronidazole twin ester prodrugs: Synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity
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A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as R(m), values, were determined using reversed- phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20% rat liver homogenate) at 37 °C using HPLC. In all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k1 and k2) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t(1/2) ~ 25-72 h) and also at the physiological pH (t(1/2) ~ 13-40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t(1/2) ~ 10-150 min) and in rat liver homogenate (t(1/2) ~ 4-55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t(1/2) ~ 3-9 h and 1-11 h respectively). In vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazote for oral drug delivery.
- Mahfouz, Nadia M.,Aboul-Fadl, Tarek,Diab, Ahmed K.
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p. 675 - 683
(2007/10/03)
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