Structure-activity relationship studies of indole-based compounds as small molecule HIV-1 fusion inhibitors targeting glycoprotein 41

Abstract

We previously described indole-containing compounds with the potential to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane glycoprotein gp41. Here we report optimization and structure-activity relationship studies on the basic scaffold, defining the role of shape, contact surface area, and molecular properties. Thirty new compounds were evaluated in binding, cell-cell fusion, and viral replication assays. Below a 1 μM threshold, correlation between binding and biological activity was diminished, indicating an amphipathic requirement for activity in cells. The most active inhibitor 6j exhibited 0.6 μM binding affinity and 0.2 μM EC50 against cell-cell fusion and live virus replication and was active against T20 resistant strains. Twenty-two compounds with the same connectivity displayed a consensus pose in docking calculations, with rank order matching the biological activity. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion and demonstrates a potent low molecular weight fusion inhibitor.

Figure 1

Structure of lead compounds 1a and 1b.

Scheme 1. Synthesis of Bisindole Compounds

Scheme 2. Synthesis of Benzimidazole–Indoles

Scheme 3. Synthesis of 3-Substituted Indoles

Scheme 4. Synthesis of Truncated Bisindoles

Figure 2

Four-ring system compounds with 6–6′ bisindole and 1,1′-benzyl linkages, docked using FRED 2.2.5 into PDB structure 2XRA (five-helix, antibody HK20 binding site). (A) Shown overlaid are 1a, 6a–d, 6f, 6h–k, 10a–b. (B) 6j docked in the binding site.

Figure 3

OEChemScore plotted against observed EC₅₀^VCF for molecules in Tables 1 and 2. Scores of the lowest energy conformer selected by FRED docking are included for three categories described in the text: (1) 6–6′ linked bisindole compounds, 3-substituted bisindoles with complementary shape, and all three-ring systems (black); (2) benzimidazole containing compounds and alternatively linked bisindole compounds (red); (3) outliers not included in the calculation of correlation coefficient (green). The data for this graph are provided in the Supporting Information.