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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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

De Luca L,De Grazia S,Ferro S,Gitto R,Christ F,Debyser Z,Chimirri A

doi

10.1016/j.ejmech.2010.12.012

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

756-64

issue

2

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(10)00868-8

journal_volume

46

pub_type

杂志文章

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