title: HIV-1 integrase strand-transfer inhibitors: design, synthesis and molecular modeling investigation.
abstract: 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.
authors.affiliation: Dipartimento Farmco-Chimico, University of Messina, Viale Annunziata, I-98168 Messina, Italy. ldeluca@unime.it
authors.forename: Laura
authors.initials: L
authors.lastname: De Luca
authors.forename: Sara
authors.initials: S
authors.lastname: De Grazia
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferro
authors.forename: Rosaria
authors.initials: R
authors.lastname: Gitto
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011760:Pyrrolidinones / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D007211:Indoles; D011760:Pyrrolidinones; D015363:Quinolones; C000164:1-benzylindole; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1