126613-32-9Relevant articles and documents
PROTEIN BINDING COMPOUNDS
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Page/Page column 20, (2010/02/11)
The present invention provides a prodrug compound comprising a therapeutically effective moiety coupled via a metabolically cleavable bond to a blood protein binding moiety.
Metronidazole twin ester prodrugs II: Non identical twin esters of metronidazole and some antiprotozoal halogenated hydroxyquinoline derivatives
Aboul-Fadl, Tarek,Mahfouz, Nadia M.
, p. 309 - 324 (2007/10/03)
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.
Metronidazole twin ester prodrugs: Synthesis, physicochemical properties, hydrolysis kinetics and antigiardial activity
Mahfouz, Nadia M.,Aboul-Fadl, Tarek,Diab, Ahmed K.
, p. 675 - 683 (2007/10/03)
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.
