Nitrogen positional scanning in tetramines active against HIV-1 as potential CXCR4 inhibitors
Author
Borrell Bilbao, José Ignacio
Puig de la Bellacasa Cazorla, Raimon
Gibert Bosch, Albert
Planesas, Jesús M.
Ros Blanco, Laia
Batllori Aguilà, Xavier
Badía, Roger
Clotet i Sala, Bonaventura
Esté, José A.
Teixidó i Closa, Jordi
Other authors
Universitat Ramon Llull. IQS
Publication date
2015-12Abstract
The paradigm, derived from bicyclams and other cyclams, by which it is necessary to use the p-phenylene moiety as the central core in order to achieve high HIV-1 antiviral activities has been reexamined for the more flexible and less bulky structures 4, previously described by our group as potent HIV-1 inhibitors. The symmetrical compounds 7{x,x} and the non-symmetrical compounds 8{x,y} were designed, synthesized and biologically evaluated in order to explore the impact on the biological activity of the distance between the phenyl ring and the first nitrogen atom of the side chains. EC50 exactly followed the order 7{x,x} < 8{x,x} < 4{x,x} indicating that, for such flexible tetramines, the presence of two methylene units on each side of the central phenyl ring increases the biological activity contrary to AMD3100. A computational study of the interactions of 4{3,3}, 7{3,3} and 8{3,3} with CXCR4 revealed interactions in the same pocket region with similar binding modes for 4{3,3} and 7{3,3} but a different one for 8{3,3}.
Document Type
Article
Published version
Language
English
Subject (CDU)
547 - Organic chemistry
Keywords
Nitrogen--Inhibidors
VIH (Virus)
Nitrogen
Inhibitors
Human immunodeficiency virus
HIV (Viruses)
Pages
18 p.
Is part of
Organic & Biomolecular Chemistry. Vol.14, n.4 (2016), p.1455-1472
Grant agreement number
info:eu-repo/grantAgreement/MINECO/PN I+D/SAF2010-C21617-C02
info:eu-repo/grantAgreement/MINECO/PN I+D/BFU2012-31569
info:eu-repo/grantAgreement/MINECO/PN I+D/FIS PI13/01083
This item appears in the following Collection(s)
Rights
© The Royal Society of Chemistry
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/