SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor

Abstract

We describe structure-activity relationship and optimization studies of RN-18, an HIV-1 Vif-APOBEC3G axis inhibitor. Targeted modifications of RN-18 ring-C, ring-B, ring-A, bridge A-B, and bridge B-C were performed to identify the crucial structural features, which generated new inhibitors with similar (<b>4g</b> and <b>4i</b>) and improved (<b>5</b>, <b>8b</b>, and <b>11</b>) activities. Two potent water-soluble RN-18 analogues, <b>17</b> and <b>19,</b> are also disclosed, and we describe the results of pharmacological studies with compound <b>19.</b> The findings described here will be useful in the development of more potent Vif inhibitors and in the design of probes to identify the target protein of RN-18 and its analogues.