HI-236

The synthesis of bifunctional compound 10 consisting of d4U joined at C-5 to a butynyl spacer attached to HI-236 is reported using a Sonogashira coupling as a key step. As a non-cleavable bifunctional HIV inhibitor incorporating an NRTI with an NNRTI, 10 shows good inhibitory activity (EC(50)=250 nM) against HIV (IIIB) replication in MT-2 cell culture, which is eight times greater than that of d4T and between those of the two component drugs.

Several thiourea derivatives have been found to possess biol. activity.In particular, phenethyl thiazolyl thiourea derivatives with a heterocyclic ring exhibit potent antiviral activity.These thiourea derivatives were also found to inhibit RT, the reverse transcriptase enzyme, by binding the non-nucleoside inhibitor site of RT.To better understand the nature of the binding of these compounds a detailed crystal structure anal. on these thiourea compounds was undertaken.Here, we report the results of our X-ray crystal structure study of substituted thiourea compoundsComparison of the hydrogen bonding characteristics exhibited by structurally distinct thiourea analogs was informative concerning their inter- and intramol. hydrogen bonding.Addnl., we found that among the thioureas studied, the 2,5-dimethoxy substituted phenethyl thiourea had strong intramol. hydrogen bonding forming a nine-member ring in the crystal lattice that was absent in the other methoxy substituted phenethyl thioureas examinedComparison of the structures demonstrated that the presence of a heterocyclic nitrogen atom in the ring results in the formation of a stable six-member ring rather than a nine-member ring.