Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin

SCHENFELD, E.; RIBONE, S. R.; QUEVEDO, M. A.

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018

0928-0987

espite its vastly demonstrated clinical efficacy, zidovudine (AZT) exhibits several suboptimal pharmacokinetic properties. In particular, its short plasmatic half-life (t1/2 ~ 1 h) is related to its low bound fraction to whole plasmatic proteins and in particular to human serum albumin (HSA). The design of prodrugs constitutes a promising strategy to enhance AZT pharmacokinetic properties, including its affinity for HSA. Recently, we reported the synthesis and chemical stability evaluation of three novel prodrugs of AZT obtained by derivatization with dicarboxylic acids (1?3). In this work, we present the design, synthesis and evaluation of chemical and enzymatic stabilities of a novel series of double prodrugs of AZT obtained by derivatization of 1?3 with a methylated l-phenylalanine moiety (4?6). In addition, the plasmatic protein binding properties were studied both by experimental and theoretical techniques. Prodrugs 4?6 were found to be relatively stable at pH 7.4 (t1/2 between 4