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Synthesis of P1 '-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol

Författare

  • Maria De Rosa
  • Johan Unge
  • Hitesh V. Motwani
  • Asa Rosenquist
  • Lotta Vrang
  • Hans Wallberg
  • Mats Larhed

Summary, in English

Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macro-cyclization, 14- and 15-membered macrocyclic Pis were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 101, with a 2-thiazoly1 group in the P1' position, was the most potent PI of this new series (K-1 2.2 nM, EC50 0.2 mu M). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.

Publiceringsår

2014

Språk

Engelska

Sidor

6444-6457

Publikation/Tidskrift/Serie

Journal of Medicinal Chemistry

Volym

57

Issue

15

Dokumenttyp

Artikel i tidskrift

Förlag

The American Chemical Society (ACS)

Ämne

  • Medicinal Chemistry

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1520-4804