Kinetics and mechanism of the hydrolytic degradation of indinavir: Intramolecular catalysis

✍ Scribed by Maria M. Toteva; Roger Zanon; Drazen Ostovic

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 173 KB
• Volume: 97
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.21259

✦ Synopsis

The pH-rate profile of first-order rate constants for the lactonization of Indinavir in aqueous solutions with ionic strength I ¼ 1 (KCl) at 408C is reported. The lactonization reaction is a subject of strong buffer catalysis with a nonlinear dependence of the first-order rate constants on the concentration of the buffer. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple peptides and for the intramolecular OH-catalyzed hydrolysis of g-hydroxyamides. This complexity appears unique to Indinavir and is a result of the cis-aminoindanol leaving group. The mechanistic pathways for the lactonization are discussed. The buffer catalysis data are consistent with kinetic general acid catalysis. The second-order rate constant for the specific-acid catalyzed hydrolysis of Indinavir at 408C (k H ¼ 2.2 Â 10 À4 M À1 min À1 ) is similar to that for a simple peptide indicating similar interactions in the rate limiting transition state for both reactions.