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Title: Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones
Authors: Petricci, Elena 
Mugnaini, Claudia 
Botta, Maurizio 
Togninelli, A.
Bernardini, C.
Manetti, Fabrizio 
Parlato, M. C.
Renzulli, M. L.
Alongi, M.
Falciani, C.
Corelli, Federico 
Botta, Maurizio 
Keywords: Anti-HIV; Combinatorial chemistry; Microwave-assisted organic synthesis; Pyrimidinones; S-DABOs; Solid phase organic synthesis; Solution phase parallel synthesis; Virtual libraries
Issue Date: 2006
Project: None 
Journal: ARKIVOC
The present paper describes the application of modern combinatorial and microwave assisted techniques for the lead discovery and optimization of novel non-nucleoside HIV-1-RT inhibitors. Starting from the parallel solid phase synthesis of highly substituted pyrimidinone derivatives, compound 12c was identified as interesting lead compound for further structure optimizations. The generation and screening of a small virtual combinatorial library led to the optimization of the lead structure 12c to give highly active derivatives (against HIV1-RT wild-type and mutant strains) in the nanomolar range. Moreover, a straightforward three-step parallel solution phase approach was developed for the generation of a small library of novel 4-dialkylamino-2-methylsulfonyl-6- vinylpyrimidines which were obtained in high yield after a simple ethyl acetate extraction with no need of further purification. Surprisingly, some of these derivatives showed a new competitive inhibition of HIV1-RT never reported in the literature for this class of compounds. Molecular modeling calculations were also performed to investigate the binding mode of all synthesized compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity.
ISSN: 1551-7012
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