Synthesis and evaluation of "AZT-HEPT", "AZT-pyridinone", and "ddC-HEPT" conjugates as inhibitors of HIV reverse transcriptase

To test the concept that HIV reverse transcriptase could be effectively inh ibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component(AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication. The (N-3 and C-5)AZT-HEPT conj ugates 15, 22, and 23 displayed 2-5 mu M anti-HIV activity, but they had no effect on the replication of HIV-2 or the HIV-1 strain with the Y181C muta tion. The (C-5)AZT-pyridinone conjugates 34-37 were found to be inactive. I n marked contrast, the ddC-HEPT molecule 26 displayed the same potency (EC5 0 = 0.45 mu M) against HTV-1 (wild type and the Y181C nevirapine-resistant strain) and HIV-2 in cell culture. No synergistic effect was-observed for t hese bis-substrate inhibitors, suggesting that the two individual inhibitor components in these molecules do not bind simultaneously in their respecti ve sites. Interestingly, however, the results indicate that the AZT-HEPT co njugates and the ddC-HEPT derivative 26 inhibit reverse transcriptase (RT) in an opposite manner. One explanation for this difference is that the form er compounds interact preferentially with the hydrophobic pocket in RT, whe reas 26 (after supposed triphosphorylation) inhibits RT through binding in the catalytic site.