Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives

Abstract 4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1 H -indol-3-yl)ethane-1,2-dione ( 2 and 3 , respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined in the context of compounds 6a–ah . The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120.