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

De Rosa, Maria; Unge, Johan LU ; Motwani, Hitesh V.; Rosenquist, Asa; Vrang, Lotta; Wallberg, Hans and Larhed, Mats (2014) In Journal of Medicinal Chemistry 57(15). p.6444-6457
Abstract
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.
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
57
issue
15
pages
6444 - 6457
publisher
American Chemical Society (ACS)
external identifiers
  • wos:000340445900014
  • scopus:84906099005
ISSN
1520-4804
DOI
10.1021/jm500434q
language
English
LU publication?
yes
id
617b6452-ce9d-47ca-8a6a-d872139340ce (old id 4649041)
date added to LUP
2014-09-24 09:30:06
date last changed
2017-10-22 03:30:44
@article{617b6452-ce9d-47ca-8a6a-d872139340ce,
  abstract     = {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.},
  author       = {De Rosa, Maria and Unge, Johan and Motwani, Hitesh V. and Rosenquist, Asa and Vrang, Lotta and Wallberg, Hans and Larhed, Mats},
  issn         = {1520-4804},
  language     = {eng},
  number       = {15},
  pages        = {6444--6457},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Synthesis of P1 '-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol},
  url          = {http://dx.doi.org/10.1021/jm500434q},
  volume       = {57},
  year         = {2014},
}