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Synthesis of 6‐(3,5‐Dichlorobenzyl) Derivatives as Isosteric Analogues of the HIV Drug 6‐(3,5‐Dimethylbenzyl)‐1‐(ethoxymethyl)‐5‐isopropyluracil (GCA‐186)
Author(s) -
Sørensen Esben R.,
ElBrollosy Nasser R.,
Jørgensen Per T.,
Pedersen Erik B.,
Nielsen Claus
Publication year - 2005
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200400952
Subject(s) - moiety , stereochemistry , chemistry , human immunodeficiency virus (hiv) , mutant , alkoxy group , drug , reverse transcriptase , methyl group , biological activity , biochemistry , in vitro , biology , pharmacology , organic chemistry , virology , rna , group (periodic table) , alkyl , gene
The HIV‐1 inhibitors described in this paper is closely related to 6‐(3,5‐dimethylbenzyl)‐1‐(ethoxy methyl)‐5‐isopropyluracil (GCA‐186) an anti‐HIV‐1 drug that is highly active against both wild type and mutated HIV‐1 strains. The two methyl groups on the 6‐benzyl moiety have been shown to improve the binding stability of the drug to the NNRTI‐binding site in reverse transcriptase of drug mediated mutant HIV‐1 viruses. The methyl groups are replaced with isosteric chloro‐atoms to avoid metabolism due to the two methyl groups. However, the isosteric chloro derivatives show tenfold less activity against HIV‐1 than their corresponding methyl derivatives. The synthesis and the antiviral activities of the corresponding 1‐(allyloxy‐ and indanyloxy)methyl‐6‐(3,5‐dichlorobenzyl)‐5‐ethyluracil derivatives are also reported.