Chiral resolution and molecular modeling investigation of rac-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.

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.

[1]  W. C. Still,et al.  The GB/SA Continuum Model for Solvation. A Fast Analytical Method for the Calculation of Approximate Born Radii , 1997 .

[2]  E Novellino,et al.  Structure-based design, synthesis, and biological evaluation of conformationally restricted novel 2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones as non-nucleoside inhibitors of HIV-1 reverse transcriptase. , 2001, Journal of medicinal chemistry.

[3]  D. Lightner.  Chapter 5 Determination of absolute configuration by CD. Applications of the Octant Rule and the Exciton Chirality Rule , 1994 .

[4]  Richard T. Walker,et al.  Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. , 1996, Journal of medicinal chemistry.

[5]  C. Conti,et al.  Enatioseparation and anti-rhinovirus activity of 3-benzylchroman-4-ones. , 1999, Chirality.

[6]  P. Timmermans.  Stereochemistry and Biological Activity of Drugs , 1983 .

[7]  A. Mai,et al.  3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs): A New Class of Specific Inhibitors of Human Immunodeficiency Virus Type 1 , 1993 .

[8]  C. Djerassi,et al.  Optical Rotatory Dispersion Studies. C.1 Variable-Temperature Circular Dichroism Studies of Ring-Conformational and Rotational Equilibria in Cyclohexanones2 , 1965 .

[9]  A. Mai,et al.  Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines: novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series. , 1997, Journal of medicinal chemistry.

[10]  A. Mai,et al.  Synthesis and anti-HIV-1 activity of thio analogues of dihydroalkoxybenzyloxopyrimidines. , 1995, Journal of medicinal chemistry.

[11]  J Desmyter,et al.  Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. , 1988, Journal of virological methods.

[12]  E. Novellino,et al.  5-Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3, 4-dihydropyrimidin-4(3H)-ones: novel potent and selective dihydro-alkoxy-benzyl-oxopyrimidine derivatives. , 1999, Journal of medicinal chemistry.

[13]  A. Mai,et al.  Synthesis and Antiviral Activity of New 3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs), Specific Inhibitors of Human Immunodeficiency Virus Type 1 , 1995 .

[14]  G. Chang,et al.  Macromodel—an integrated software system for modeling organic and bioorganic molecules using molecular mechanics , 1990 .

[15]  W. C. Still,et al.  Semianalytical treatment of solvation for molecular mechanics and dynamics , 1990 .