Comparative molecular field analysis (CoMFA) has been applied to a large set of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues. The starting geometry of HEPT was obtained from crystallographic data of HEPT/HIV-1 reverse transcriptase (RT) complexes. The structures of 101 HEPT derivatives were considered and fully optimized by ab initio molecular orbital calculations at the HF/3-21G level. The best CoMFA model is satisfactory in both statistical significance and predictive ability. It shows excellent, high predictive ability as r2cv = 0.858. The derived model indicates the importance of steric contributions (64.4%) as well as electrostatic interactions for the HIV-1 RT inhibition. In addition, steric and electrostatic contour maps from this analysis agree well with the experimentally observed trend that there are steric interactions between the side chain of HEPT and an aromatic ring of Tyr181. It is concluded that a moderately sized group at C5 enhances contact with Tyr181 enough to push it into a position which renders the protein nonfunctional, but a smaller group has insufficient steric requirements to do this and a larger group renders the ligand too large for the cavity. The mutation-induced resistance of reverse transcriptase is explained by this analysis. The obtained results not only lead to a better understanding of structural requirements of this set of compounds for the inhibition but also enable the suggestions for new and more potent drugs.

5,6,7,8-Tetrafluoro-3lambda4delta2,1,2,4-benzothiaselenadiazine (1) is prepared by the intramolecular nucleophilic cyclization of C6F5SeN=S=NSiMe3 (2) mediated by CsF. According to an X-ray diffraction analysis, the heterocycle of 1 is bent along the Se(1)...N4 line by 6.0(2) degrees in the crystal. Despite the obvious similarities between 1 and its 1,3-dithia analogue (7) with respect to molecular composition and shape, the crystal packing of 1 is substantially different from that of 7. An interesting consequence of this is the inclusion of atmospheric N2 in the crystal lattice of the selenium derivative 1. The molecular structure and bonding of 1 have been investigated using quantum-chemical calculations at the DFT/B3LYP/6-311+G level of theory, and the results have been compared to those of 5,6,7,8-tetrafluoro-1,3lambda4delta2,2,4-benzodithiadiazine (7) and their hydrocarbon analogues (5 and 8).