Abstract: Theoretical study on the hydrolysis mechanism of N,N-bis(p-fluorobenzyl)-N′-(2′,3′- dideoxy-3′-thiacytidinyl)formamidine(FBFA-3TC) was carried out at the B3LYP/6-31G(d,p) level. The solvent effect was evaluated using the conductor polarizable continuum model(CPCM) through the single point energy calculations at the B3LYP/6-31++G(d,p) level. Two reaction pathways are considered. Path A is the addition of water molecule to the C=N double bond in the amidine group in its first step and Path B is the attack of water molecule to the C-N single bond in its first step. The calculated results indicate that the first step in both pathways is the rate-limiting process and Path A is more favorable than Path B in the gas phase and in water. The solvent effects are not distinct. It is also found that the second step in Path A proceeds preferably according to Channel a, in which the second H atom of water transfers to the N atom in double bond of the amidine group, leading to products the modified cytidine and N,N-dibenzyl formamide.

Key words: N,N-Bis(p-fluorobenzyl)-N′-(2′,3′-dideoxy-3′-thiacytidinyl)formamidine, Hydrolysis, Density functional theory, Conductor polarizable continuum model(CPCM)