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

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 ( 4g and 4i ) and improved ( 5, 8b, and 11 ) activities. Two potent water-soluble RN-18 analogues, 17 and 19, are also disclosed, and we describe the results of pharmacological studies with compound 19 . 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.