HIV-1 integrase strand-transfer inhibitors: Design, synthesis and molecular modeling investigation

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.

Graphical abstractA novel series of benzylindole derivatives, suggested by molecular modeling studies, was synthesized and evaluated for their anti-retroviral activity.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► HIV-1 is the etiological agent of Immunodeficiency Acquired Syndrome (AIDS). ► HIV-1-IN plays a key role in stable infection. ► A novel series of benzylindole derivatives was designed and synthesized. ► The strand-transfer IN step was inhibited at nanomolar concentration. ► The key role of some structural requirements for binding between IN and STIs has been demonstrated.