ABSTRACT:
Purpose: In the present study ester conjugates of a protease inhibitor, Atazanavir (AT) were prepared with various amino acids to improve its physicochemical, pharmacokinetic and safety profile. Methods: All the conjugates were synthesized by dicyclohexyl carbodiimide (DCC) coupling method using dimethylaminopyridine as a catalyst. The synthesized compounds were characterized by NMR, mass, FTIR spectroscopy and elemental analysis and evaluated for their solubility, partition coefficient and hydrolytic stability. Cytotoxicity and permeability studies were carried out across Caco-2 cell line. The synthesized derivatives were screened for anti-HIV activity by protease inhibition assay. Results: Solubility studies indicated that all the conjugates have greater water solubility as compared to AT. Conjugates displayed higher stability under acidic conditions while undergo hydrolysis as the pH is increased. Absorptive diffusion across Caco-2 cell monolayers was improved and recognition by efflux carriers was reduced by amino acid conjugation. No cytotoxicity was detected for conjugates upto concentration as high as 100µg/ml, which indicates better safety profile and promising therapeutic potential. Conclusion: Direct conjugation of L-amino acids has the potential to improve oral absorption and thereby oral bioavailability of protease inhibitors.