Chiral resolution and molecular modeling investigation ofrac-2-cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047), a potent anti-HIV-1 reverse transcriptase agent of the DABO class

Abstract

rac-2-Cyclopentylthio-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methylpyrimidin-4(3H)-one (MC-1047) is a potent inhibitor of HIV-1 multiplication in acutely infected cells. MC-1047 racemate has been resolved by chiral HPLC using, as chiral stationary phase (CSP), a commercially available (R,R)-Whelk-01 column. The optical purity and the circular dichroism (CD) of the two resolved enantiomers were determined and their biological activities tested in in vitro assays. Molecular modeling inspection of the binding of (R) and (S) enantiomers to the non-nucleoside binding site (NNBS) of reverse transcriptase (RT) using the defined model of F(2)-S-DABO/RT complex indicates the (R) enantiomer as the more active isomer.

Synthesis, X-ray crystal structure study and antitumoral evaluations of 5,6-disubstituted pyrimidine derivatives

“…5-Substituted uracil analogs have been investigated extensively for use in cancer 1,2 and viral chemotherapy, 3,4 as enzyme inhibitors [5][6][7][8] and in the synthesis of modified nucleotides. 9,10 In addition, pyrimidines substituted at position C-6, as for example, 1-[(2-hydroxyethyl)-methyl]-6-(phenylthio)thymine (HEPT) 11,12 or 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) 13 and their derivatives [14][15][16] exhibited a potent and selective activity against human immunodeficiency virus type-1 (HIV-1). Although these compounds are relatively simple from a structural point of view, they have been the subject of great deal of chemical work.…”

“…25 Therefore, biological activities by both 5-substituted and 6-substituted uracil derivatives encouraged us to explore chemistry and biological activities of novel 5,6-disubstituted uracil derivatives. In this paper we present syntheses, X-ray crystal structural study and cytostatic evaluations of pyrimidine derivatives (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) bearing substituents at positions C-5 and C-6 of pyrimidine ring (Figure 1). a-(1-Carbamyliminomethylene)-c-butyrolactone (2) was prepared by condensation of a-acetyl-c-butyrolactone (1) with urea in ethanol.…”

“…In this reaction monochlorinated (15) and dichlorinated (16) pyrimidines were also isolated. Subsequent methoxylation of 14 using sodium methoxide yielded 2,4-dimethoxypyrimidine derivative 17 with chloroethyl substituent at C-5 of pyrimidine ring and its 5-vinyl analog 18 as a product of dehydrohalogenation.…”

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a b s t r a c t 5,6-Disubstituted pyrimidine derivatives (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were prepared by intramolecular cyclization reaction of a-(1-carbamyliminomethylene)-c-butyrolactone (2) with sodium ethoxide and subsequent chemical transformation of 2-hydroxy group in C-5 side chain as well as lithiation reaction for introduction of acyclic side chain at C-6. All compounds were characterized by 1 H NMR, 13 C NMR and mass spectra.

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Stereoselective synthesis of 2-substituted 6-[1-(2,6-difluorophenyl)ethyl]-5-methylpyrimidin-4(3H)-ones

“…It was also found that the maximal antiviral activity in the above series of compounds is intrinsic to derivatives with R configuration of the benzylic carbon atom [5]. Up to now, the only procedure reported for the preparation of optically pure 2-(cyclopentylsulfanyl)-6-[(1R)-1-(2,6-difluorophenyl)ethyl]-5-methylpyrimidin-4(3H)-one is resolution by preparative chiral chromatography [5]. There are no published data on stereoselective synthesis of this compound.…”