Crystal structure of 3,4-dihydro-6-(3'-methylbenzyl)-2-[(1-methylpropyl) thio]-4-oxopyrimidine (S-DABO 618), C16H20N2OS and of 3,4- dihydro-2-[(1-methylpropyl)thio]-6-(2-naphthylmethyl)-4-oxopyrimidine (DATNO 774), C19H20N2OS, two HIV-1 reverse transcriptase inhibitors

The DABO (dihydroalkoxybenzyloxopyrimidine), S-DABO (dihydroalkylthiobenzyloxopyrimidine) and DATNO (dihydroalkylthionaphthylmethyloxopynmidine) derivatives are non-nucleoside reverse transcriptase inhibitors (ΝΝΚΉβ) of the human immunodeficiency viras type 1 (HIV-1) (see refs. 1-4). Recent studies on crystal stractures of several Ηΐν-1/ΝΝΚΉ complexes showed that differendy designed NNRΉs have an analog binding mode (see refs. 5-8). In fact, all they adopt a similar 'butterfly-like' shape, with two hydrophobic moieties connected by a linker group that allows the two wings to bend with an angle of 110° 115°, that is considered optimal for maximum of activity. Both S-DABO 618 and DATNO 774 crystallized with difficulty giving poor quality crystals. However, obtained data are sufficient to support further 3D-QSAR (3-Dimentional Quantitative Stracture-Activity Relationship) studies on DABO, S-DABO and DATNO series. Phenyl and pyrimidine rings in S-DABO 618 have as a linker the tetrahedral carbon atom C8 whose valence angle (C3-C8-C9) is 111.9°. In DATNO 774 the Unkage is formed by the atoms C2-C6-C7 with a 114.9° angle value. Althought both these molecules assume a 'butterfly-like' conformation, they show difference in their activities, with EC50 (Effective Concentration at 50% inhibition) values of 0.54 μΜ for S-DABO 618 (see ref. 1) and 2.8 μΜ for DATNO 774 (see ref. 2). Recently we reported (see ref. 9) that in the 'butterfly-like' model a simple structural parameter such as the valence angle between the two rings has not been sufficient to explain the low activity of S-DABO 622 (EC50 = 3.3 μΜ; valence angle: 112.0°) when compared with highly active nevirapine (EC50 = 0.25 μΜ ; valence angle: 115.0°). At present, we can observe that the dihedral angle between the phenyl and pyrimidine rings for S-DABO 618 is 69.8°, while for the less active molecules DATNO 774 and S-DABO 622 the dihedral angles are 80.5° and 83.9° respectively. Further structural investigations are needed to confirm a relationship between dihedral angle and anti-HIV-1 activity. Source of material: The syntheses of S-DABO 618 and DATNO 774 are already described (see refs. 1-2). S-DABO 618 crystallized from hot n-hexane and DATNO from hot cyclohexane.