The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)-methyl group at N(1) has previously been found highly active against HIV-1. The C≡C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with higher activity against HIV-1-resistant mutants. The syntheses involved Pd-catalyzed C,C-coupling reactions, addition of disulfides, and click chemistry on the terminal C≡C bond as well as addition of bromine to the so formed internal C≡C bonds. Sonogashira coupling were performed with silylderivatized iodobenzyl alcohols which, after deprotection, were oxidized to aldehydes by means of IBX. The isomeric alcohol 37 was obtained in the Sonogashira reaction of propargyl alcohol with the N(1)-substituted (4-iodobenzyloxy)methyl derivative of the above mentioned uracil. Compound 37 turned out to be the most effective compound against problematic HIV-1 mutants. The general observation in the present work is that a combination of alkyne and aryl in the substituent at N(1) leads to highly active compounds against HIV-1.

Synthesis and anti-HIV-1 evaluation of new Sonogashira-modified Emivirine (MKC-442) analogues

LODDO, ROBERTA
2009

Abstract

The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)-methyl group at N(1) has previously been found highly active against HIV-1. The C≡C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with higher activity against HIV-1-resistant mutants. The syntheses involved Pd-catalyzed C,C-coupling reactions, addition of disulfides, and click chemistry on the terminal C≡C bond as well as addition of bromine to the so formed internal C≡C bonds. Sonogashira coupling were performed with silylderivatized iodobenzyl alcohols which, after deprotection, were oxidized to aldehydes by means of IBX. The isomeric alcohol 37 was obtained in the Sonogashira reaction of propargyl alcohol with the N(1)-substituted (4-iodobenzyloxy)methyl derivative of the above mentioned uracil. Compound 37 turned out to be the most effective compound against problematic HIV-1 mutants. The general observation in the present work is that a combination of alkyne and aryl in the substituent at N(1) leads to highly active compounds against HIV-1.
Active compounds; Anti-HIV; C-coupling reactions; Click chemistry; Deprotection; Isomeric alcohols; Methyl derivatives; Methyl group; Propargyl alcohol; Resistant mutants; Sonogashira coupling; Sonogashira reactions
File in questo prodotto:
File Dimensione Formato  
Pedersen 1385-1403 (2009).pdf

Solo gestori archivio

Tipologia: versione editoriale
Dimensione 288.9 kB
Formato Adobe PDF
288.9 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/19213
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 4
social impact