| Abstrakt: |
Target-aimed synthesis of a new class of water soluble amino acid and dipeptide derivatives of fullurene (C60 - X) for inhibition of specific virus enzymes, i.e. protease and reverse transcriptase of HIV (P HIV and RT HIV) in cell culture lytic and chronic infections was performed. Out of 13 tested substances, 8 showed inhibitory activity and 5 were effective in pharmacological doses (ID50 varied within 0.46 to 1.0 mcm/ml with respect to the lytic infection and 5.0 to 12.5 mcm/ml with respect to the chronic infection). The activity of (1), (2), (6), (7) and (8) was comparable to that of azidothymidine, a nucleozide inhibitor of RT HIV in the cell culture lytic infection. The substances also showed marked virucidal action. The cytotoxicity (survival, antiproliferative effect) varied from low to very low with respect to the rapidly dividing cells MT4 and HTHIV27 (CD50 > 200-800) and was somewhat higher with respect to PBL (CD50 > 100). The selectivity index (SI = CD50/ID50) was equal to 165-2000 for various samples. The prototype derivatives (1) and (2) had a selective (competitive) inhibitory action on the recombinant protease of HIV with IC50 = 1.25-2.76 mcM, while derivatives (1), (la) and (2) had a noncompetitive inhibitory action on the recombinant reverse transcriptase of HIV (Ki = 7.9-12.1 mM). The pharmacokinetic study of the prototype derivative (1) on laboratory animals revealed no acute or chronic toxicity up to the terminal high concentrations. As for (1), its high interspecies (mice--rabbits) relative bioavailability equal to 110% was shown. |
