5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones:  Novel Potent and Selective Dihydro-alkoxy-benzyl-oxopyrimidine Derivatives

Abstract

Molecular modeling analysis of compounds belonging to the recently published series of dihydro-alkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2, 6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (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 halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2, 6-dichloro(or 2,6-difluoro)phenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most 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 >/=5000. An excellent correlation was found 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.

Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

“…8) Thereafter, many pyrimidine derivatives emerged as anti-HIV agents. 9,10) Against the background of these reports, we undertook a search for an anti-HIV agent by the structure-activity relationship (SAR) of the 1,3-disubstituted uracil 11) . It is demonstrated that the introduction of a cyanomethyl group onto N1 of uracil is effective for anti-HIV-1 activity.…”

The Structure-Activity Relationships of 2,4(1H,3H)-pyrimidinedione Derivatives as potent HIV type 1 and type 2 inhibitors

“…6-Benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC 422, [3]) (Baba et al, 1994;De Clercq, 1999) has been tested clinically but was subsequently withdrawn due to insufficient reduction in plasma viral load in Phase III studies. Other HEPT analogues have also been described, including 6-[(3,5-dimethylbenzyl)-5-ethyl-1-(ethylthio)methyl]uracil [4] (Danel et al, 1996), 6-[(3,5-dimethylphenyl)selenyl]-1-(ethoxymethyl)-5-isopropyluracil [5] (Kim et al, 1996), 3,4-dihydro-2-sec-butoxy-6-(3,5-dimethylbenzyl)-4-oxo-pyrimi dine [6] (Mai et al, 1999), 5-ethyl-6-methyl-3-carbetoxy-4-[(3′,5′-dimethylphenyl)thio]-pyridine-2(1H)-one [7] (Dolle et al, 1995). We have previously reported the biological anti-HIV-1 activity and resistance profile of another highly potent HEPT analogue, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine and the initial identification of the first member of the pyrimidinedione series of compounds described herein (1-(3-cyclopenten-1-ylmethyl)-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)-pyrimidinedione; (Buckheit et al, 2001).…”

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

“…To expand the SAR of S-DABOs, the substitution pattern on the phenyl ring was broadly varied, as well as the length of the alkyl spacer, which was increased from one to three carbon atoms, ii) a 5-methyl group which was kept fixed in all the molecules, as a conformational constraint with the aim of enhancing the affinity for the enzyme, iii) a halogenated benzyl group at the 6 position, which was expected to improve a putative π-stacking interaction between the electron deficient benzene ring of the ligand and the electron-rich benzene ring of Tyr188 located in the NNBP of the enzyme. 46 Therefore we have set up a simple and efficient methodology for the parallel solution-phase synthesis of thiouracils 20-22 using Büchi Syncore synthesizer (Scheme 3). Potassium ethyl 2-methylmalonate (16) was partitioned into three reaction vessels and reacted with three substituted phenylacetyl imidazolides in the presence of a magnesium dichloride/triethylamine system in acetonitrile according to the Clay procedure 47 to give, after a simple liquid-phase extractive purification, the β-ketoesters 17-19.…”