In:
ChemMedChem, Wiley, Vol. 1, No. 12 ( 2006-12-11), p. 1367-1378
Abstract:
Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3 – 5 , which are related to capravirine (S‐1153), were synthesized and tested for their ability to block the replication cycle of HIV‐1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008–53 μ M . Even if compounds 3 – 5 are generally less potent than S‐1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S‐1153. Compound 4 e was the most active derivative of this series in cell‐based assays; its potency is similar to that of S‐1153 (EC 50 =8 and 3 n M , respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV‐1 RT. In fact, compounds 3 – 5 generally inhibited the viral enzyme at concentrations similar to those observed in cell‐based assays. A selected number of AThPs ( 4 k and 5 a , e ) were tested against clinically relevant drug‐resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5 e showed an approximate 240‐fold decrease in activity against Y181I, but only a 10‐fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2 , 4 e , 4 j , 4 k and 5 e into the non‐nucleoside binding site of HIV‐1 RT and to rationalize some structure–activity relationships and resistance data.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.200600119
Language:
English
Publisher:
Wiley
Publication Date:
2006
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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