jtk-303 and 1-benzylindole

This study is focused on a new series of benzylindole derivatives with various substituents at the benzene-fused ring, suggested by our 3D pharmacophore model developed for HIV-1 integrase inhibitors (INIs). All synthesized compounds proved to be active in the nanomolar range (6-35 nM) on the strand-transfer step (ST). In particular, derivative 4-[1-(4-fluorobenzyl)-5,7-dimethoxy-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acid (8e), presenting the highest best-fit value on pharmacophore model, showed a potency comparable to that of clinical INSTIs GS 9137 (1) and MK-0518 (2). The binding mode of our molecules has been investigated using the recently published crystal structure of the complex of full-length integrase from the prototype foamy virus in complex with its cognate DNA (PFV-IN/DNA). The results highlighted the ability of derivative 8e to assume the same binding mode of MK-0518 and GS 9137.

Topics: Anti-HIV Agents; Cells, Cultured; Computer Simulation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Indoles; Models, Molecular; Molecular Structure; Pyrrolidinones; Quinolones; Raltegravir Potassium; Stereoisomerism; Structure-Activity Relationship; Virus Replication