Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding analogues 10a-d with a 3-trimethylsilylalkynylbenzyl substituent and their desilylated analogues 11a-d. However, they all showed activity against HIV-1 wild type in the range of more than 10fold lower than the one of MKC-442. Moderate activity against Y181C and Y181C + K103N mutated strains was also observed and, in some cases, they were marginally better than those found for MKC-442. A few amino-DABO and S-DABO analogues were also synthesized but they were found to be inactive against HIV.

Synthesis and anti-HIV-1 activity of new MKC-442 analogues with an alkynyl-substituted 6-benzyl group

LODDO, ROBERTA
2007

Abstract

Synthesis and antiviral activities are reported of a series of 6-(3-alkynyl benzyl)-substituted analogues of MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyluracil), a highly potent agent against HIV. The 3-alkynyl group is assumed to give a better stacking of the substituted benzyl group to reverse transcriptase (RT) and this was believed to improve antiviral activity against HIV-1. The bromo derivatives, 5-alkyl-6-(3-bromo-benzyl)-1-ethoxymethyl derivatives 7a, b and 5-alkyl-6-(3-bromobenzyl)-1-allyloxymethyl derivatives 9a, b, showed activity against HIV on the same level as their corresponding analogues 10a-d with a 3-trimethylsilylalkynylbenzyl substituent and their desilylated analogues 11a-d. However, they all showed activity against HIV-1 wild type in the range of more than 10fold lower than the one of MKC-442. Moderate activity against Y181C and Y181C + K103N mutated strains was also observed and, in some cases, they were marginally better than those found for MKC-442. A few amino-DABO and S-DABO analogues were also synthesized but they were found to be inactive against HIV.
Human immunodeficiency virus (HIV-1); MKC-442; Non-nucleoside reverse transcriptase inhibitors (NNRTI); Stacking; Sonogashira coupling
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/20341
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