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Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors

Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors
Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors
HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described
Hohlfeld, Konrad
f40f3c74-b8b2-4951-bacb-ae7a4841e20b
Hohlfeld, Konrad
f40f3c74-b8b2-4951-bacb-ae7a4841e20b
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Hohlfeld, Konrad (2011) Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors. University of Southampton, Chemistry, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described

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Published date: 25 May 2011
Organisations: University of Southampton

Identifiers

Local EPrints ID: 193149
URI: http://eprints.soton.ac.uk/id/eprint/193149
PURE UUID: 304f7b9a-bd4e-4c4b-b144-25c5deb18a21
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

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Date deposited: 12 Jul 2011 10:32
Last modified: 03 Dec 2019 01:54

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