HIGHLY POTENT OXATHIIN CARBOXANILIDE DERIVATIVES WITH EFFICACY AGAINST NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS ISOLATES

The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxat hiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kin jerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob, Agents Chemother, 39:2718-2727, 1996). Fro m these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV- 1) replication and a promising candidate for further development. Thre e new UC analogs (UC040, UC82, and UC781) have been determined to inhi bit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human ce lls. Each of the compounds synergistically interacted with the nucleos ide analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudin e to inhibit HIV-1 replication. As a group, the UC compounds were foun d to be less active against viruses with the L100I, K103N, and Y181C a mino acid changes in the RT and, upon in vitro selection, yielded resi stant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nano molar concentrations. Furthermore, UC781 and the NNRTI costatolide wer e able to synergistically inhibit HIV-1 replication when used in combi nation, suggesting that UC781 may interact with the RT differently tha n the other UC analogs. The favorable anti-HIV properties of the UC co mpounds suggest they should be considered for further clinical develop ment.