تصنيع ودراسة المواصفات ل الأدوية المساعده المصممة ل حمض ترانزاميك و براسيتامول
Synthesis and Characterization of Designed Tranexamic Acid and Paracetamol Prodrugs
هبه نعيم خميس غريب
hiba naeem khamees ghareeb
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Prodrug is a chemical devise in which the drug is covalently linked to a chemical moiety; this linked moiety will temporarily affect the physicochemical properties of the drug for increasing their usefulness or decreasing their toxicity. The prodrug should be converted to its active form by metabolic or/and chemical processes, conversion process involves metabolism by enzymes distributed throughout the body. These enzymes might either decrease the drug’s bioavailability, or a genetic polymorphisms might lead to variability in prodrug activation and thus affect the efficacy and safety of designed prodrug. In the past few decades computational chemistry methods have been utilized in calculating physicochemical and molecular properties of compounds. This tool can be used to design prodrugs that chemically (intramolecular processes) interconvert to their parent drugs without any involvement of enzyme catalysis. The release of the active drug is solely dependent on the rate limiting step of the intramolecular process. Based on DFT calculations four different tranexamic acid prodrugs and three different bitter less paracetamol prodrugs were designed, synthesized and characterized using FT-IR, 1H-NMR LCMS and their in vitro intra-conversion to their parent drugs revealed that the t1/2 was largely affected by the pH of the medium. For tranexamic acid ProD 1 the experimental t1/2 values in 1N HCl, buffer pH 2 and buffer pH 5 were 54 minutes, 23.9 hours and 270 hours, respectively. Tranexamic acid ProD 2 was readily converted in 1 N HCl and pH 2 while it was entirely stable at pH 5 and pH 7.4. On the other hand, tranexamic acid ProD 3 and Prod 4 were stable in all media studied. The experimental t1/2 values for paracetamol ProD 2 in pH 3 and pH 7.4 were 3 hours and 18 minutes respectively and for paracetamol ProD 3 it was 27 hours in pH 3 and 12 hours in pH 7.4. In vitro binding for paracetamol ProD 2 to bitter taste receptors revealed that this prodrug lacks any binding affinity and it was found not to have any bitter sensation. This suggests, that paracetamol ProD 2 can replace its parent drug, paracetamol, for the use asbitterless antipyretic drug for geriatrics and pediatrics.