Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents

Kitchin, John R.; Bethell, Richard C.; Cammack, N.; Dolan, Simon; Evans, Derek N.; Holman, Stuart; Holmes, Duncan S.; McMeekin, Peter; Mo, Chi L.

doi:10.1021/jm00048a007

Cited by 11 publications

(1 citation statement)

References 9 publications

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“…Here are some examples of original attempts to find nonpeptide HIV-1 PR inhibitors. Novel series of penicillinderived C 2 -symmetric inhibitors of HIV-1 PR were identified (as exemplified by compound 21) [98][99][100][101][102]. Although the compounds were selective and exhibited no cytotoxicity, they suffered from rapid elimination.…”

Section: Screening Approachmentioning

confidence: 99%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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Recently, western countries have recorded a decrease in the death rate imputed to AIDS. This success has been largely attributed to the presence on the market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for viral replication. Two main sites have been identified as potential targets for the inhibition of HIV-1 PR, the active site and the interface, the latter being largely responsible for the stabilization of the enzyme dimeric structure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analogues and result from modifications of the peptidic scaffold into peptidomimetics. In order to improve their bioavailability, systematic biological screening and de novo design have been used to suggest new non-peptide inhibitors combining both antiviral potency and favorable pharmacokinetic properties. In parallel, compounds targeting other potential sites of inhibition have been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutations, have been shown to lead to HIV-1 PR inactivation. Cupric ion was described to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.

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Section: Screening Approachmentioning

confidence: 99%

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Lebon¹,

Ledecq

2000

CMC

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Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

Breuning

Hein

Steiner

et al. 2009

Chemistry A European J

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A flexible approach, applicable on a gram scale, to chiral 2-endo-substituted 9-oxabispidines was developed. The key intermediate, a cis-configured 6-aminomethylmorpholine-2-carbonitrile, was prepared from (R)-3-aminopropane-1,2-diol and 2-chloroacrylonitrile. The 2-endo substituent was introduced by Grignard addition, cyclization, and exo-selective reduction, thus furnishing the enantiomerically pure bi- and tricyclic 9-oxabispidines in 19-59 % yield. The CuCl(2) complex of the tricyclic 9-oxabispidine, which carries an 2-endo,N-anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S-configured beta-nitro alcohols in 91-98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9-oxabispidines delivered the enantiocomplementary R-configured products in 33-57 % ee. The respective transition states were discussed.

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Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets

Ohtaka

2004

The International Journal of Biochemistry & Cell Biology

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Synthesis and Structure-Activity Relationships of a Series of Penicillin-Derived HIV Proteinase Inhibitors: Heterocyclic Ring Systems Containing P1' and P2' Substituents

Cited by 11 publications

References 9 publications

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Approaches to the Design of Effective HIV-1 Protease Inhibitors

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets

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