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S. J. Shah, R. Talluri, S. Katragadda, A. K. Mitra; Synthesis, Stability and Antiviral Activity of Aminoacid Ester Prodrugs of Acyclovir and Their Utility in Treatment of Herpes Keratitis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5131.
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© ARVO (1962-2015); The Authors (2016-present)
To synthesize and study the buffer stability, enzymatic stability and antiviral activity against Herpes simplex virus and varicella zoster virus of aminoacid ester prodrugs of acyclovir (ACV).
Aminoacid ester prodrugs of ACV, L-alanine-ACV (AACV), L-serine-ACV (SACV), L-serine-succinate-ACV (SSACV) and L-cysteine-ACV (CACV) were synthesized. Products were confirmed by NMR and LC-MS/MS. Stability of the prodrugs was studied in Dulbecco’s phosphate buffer saline (DPBS) prepared at different pH values (5-7.4). Hydrolysis of the prodrugs was studied in rabbit corneal tissue homogenates. The in vitro potencies of the parent drug, ACV, and the prodrugs, AACV, SSACV, SACV, and CACV were determined against various herpes viruses.
All the products were synthesized and characterized. The pH of maximal stability within the range studied was 5.0. The half-lives for AACV, CACV SSACV and SACV in DPBS pH 7.4 were 2.88 ± 0.07, 3.1 ± 0.3, 38 ± 11.6 and 29.3 ± 2.7 hrs respectively. AACV was readily converted to the active parent drug acyclovir exhibiting complete degradation before 5 min period. The half lives of SSACV, SACV and CACV (t1/2) 3.5 ± 0.4, 9.2 ± 0.6 and 1.8 ± 0.1 hr respectively. SACV, CACV and AACV showed excellent antiviral activity against HSV-1 with an EC50 of 6.3, 5.4, and 6.6 µM respectively relative to 7.1 µM for ACV and 9.1 µM for VACV.
Amino acid esters of ACV with high chemical stability, ability to generate ACV in corneal homogenates and potent antiviral activity seems to be promising candidates for the treatment of herpes keratitis.
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