RATIONAL DESIGN AND SYNTHESIS OF PHENETHYL-5-BROMOPYRIDYL THIOUREA DERIVATIVES AS POTENT NONNUCLEOSIDE INHIBITORS OF HIV REVERSE-TRANSCRIPTASE

A series of novel phenethylthiazolylthiourea (PETT) derivatives target ing the nonnucleoside inhibitor (NNI) binding site of HIV reverse tran scriptase (RT) have been designed based on the structure of the NNI bi nding pocket. The structure-based design and synthesis of these new PE TT derivatives were complemented by biological assays of their anti-HI V activity. Modeling studies for rational drug design included the con struction of a composite NNI binding pocket from nine RT-NNI crystal s tructures, the analyses of surface complementarity between NNI and RT, and application of K-i calculations combined with a docking procedure involving the novel PETT derivatives. The use of the composite NNI bi nding pocket allowed the identification and structure-based design of three promising PETT derivatives with ortho-F (2), ortho-Cl (3), and m eta-F (5) substituents on the phenyl ring. These novel PETT derivative s were more active than AZT or trovirdine and showed potent anti-HIV a ctivity with IC50[p24] values of <1 nM and selectivity indices of > 10 0,000. (C) 1998 Elsevier Science Ltd. All rights reserved.