Dihydro - alkoxy - benzyl - oxopyrimidines (DABOs) were disclosed as NNRTIs by our group in 1993. Although not very potent (EC50 ranged from 3.0 to 40.0μM), they resulted scarcely cytotoxic (CC50 was >200μM) thus encouraging further studies with the aim to increase their potency. As a result, a new series ofDABO derivates bearing 3-methyl or 3, 5-dimethylbenzyl moiety as substituent at the C-6 position of the pyrimidine ring have been prepared and tested for anti-HIV-1 activity. In vitro, the most potent compounds had an EC50 of 0.8 μM and a selective index of 400. The next step was to evaluate the effect on antiviral activity produced by replacing the alkyloxy chain with the corresponding alkylthio chain(S-DABOs). Among these novel derivatives many showed EC50 values as low as 0.6 μM and lacked cytotoxicity at doses as high as 200 μM. Further improvement in potency was obtained through the substitution of the benzyl moiety with a naphthylmethyl group (DATNOs). More recently, molecular modeling studies prompted the synthesis and biological evaluation of novel DABOs bearing fluorine or chlorine atoms at positions 2 and 6 of the benzene ring. The most potent derivatives we obtained were 2,6-diflurobenzyl analogs of S-DABOs, some of which were found to be endowed with anti HIV-1 activity at nanomolar concentrations(EC50 5nM,SI>40,000).

3,4-Dihydro-2-alkoxy-6-benzyl-oxopyrimidines [DABOs]: Development of a potent class of non-nucleoside reverse transcriptase inhibitors

SBARDELLA, Gianluca;
2001

Abstract

Dihydro - alkoxy - benzyl - oxopyrimidines (DABOs) were disclosed as NNRTIs by our group in 1993. Although not very potent (EC50 ranged from 3.0 to 40.0μM), they resulted scarcely cytotoxic (CC50 was >200μM) thus encouraging further studies with the aim to increase their potency. As a result, a new series ofDABO derivates bearing 3-methyl or 3, 5-dimethylbenzyl moiety as substituent at the C-6 position of the pyrimidine ring have been prepared and tested for anti-HIV-1 activity. In vitro, the most potent compounds had an EC50 of 0.8 μM and a selective index of 400. The next step was to evaluate the effect on antiviral activity produced by replacing the alkyloxy chain with the corresponding alkylthio chain(S-DABOs). Among these novel derivatives many showed EC50 values as low as 0.6 μM and lacked cytotoxicity at doses as high as 200 μM. Further improvement in potency was obtained through the substitution of the benzyl moiety with a naphthylmethyl group (DATNOs). More recently, molecular modeling studies prompted the synthesis and biological evaluation of novel DABOs bearing fluorine or chlorine atoms at positions 2 and 6 of the benzene ring. The most potent derivatives we obtained were 2,6-diflurobenzyl analogs of S-DABOs, some of which were found to be endowed with anti HIV-1 activity at nanomolar concentrations(EC50 5nM,SI>40,000).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/3877965
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