5-alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones: Novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives

Molecular modeling analysis of compounds belonging to the recently publishe d series of dihydroalkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs an d DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO d erivatives as highly potent and specific inhibitors of the HIV-1 reverse tr anscriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two haloge n units were introduced at positions 2 and 6 in the phenyl portion of the b enzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(o r cycloalkyl)thio)-6-(2,B-dichloro(or 2, 6-difluoro)phenylmethyl)-3,4-dihyd ropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agent s in both cell-based and enzyme (recombinant reverse transcriptase, rRT) as says. Among the various mono- and disubstituted phenyl derivatives, the mos t potent were those containing a 6-(2,6-difluorophenylmethyl) substituent ( F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to greater than or equal to 5000. An excellent correlation was f ound between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure-activity relationships of the newly synthesized pyrimidinones are presented herein.