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.

Petricci, E., Mugnaini, C., Botta, M., Togninelli, A., Bernardini, C., Manetti, F., et al. (2006). Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones. ARKIVOC, 7, 452-478.

Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones

PETRICCI, ELENA;MUGNAINI, CLAUDIA;BOTTA, MAURIZIO;MANETTI, FABRIZIO;CORELLI, FEDERICO;
2006-01-01

Abstract

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.
2006
Petricci, E., Mugnaini, C., Botta, M., Togninelli, A., Bernardini, C., Manetti, F., et al. (2006). Towards new methodologies for the synthesis of biologically interesting 6-substituted pyrimidines and 4(3H)-pyrimidinones. ARKIVOC, 7, 452-478.
File in questo prodotto:
File Dimensione Formato  
2006ARKIVOC_RT-HIV-1.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 655.48 kB
Formato Adobe PDF
655.48 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/11365/22397
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo