Design of MKC-442 (emivirine) analogues with improved activity against drug-resistant HIV mutants

Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirin e), containing different C6 substituents have been designed to be less susc eptible to the commonly found drug-resistance mutation of Tyr181Cys. Compou nd TNK-6123 had a C6 thiocyclohexyl group designed to have more flexibility in adapting to the mutated drug-binding site. GCA-186 had additional 3',5' -dimethyl substituents aimed at forming close contacts with the conserved r esidue Trp229. Both compounds showed similar to 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinica lly important Lys103Asn virus. X-ray crystallographic structure determinati on of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series ag ainst common drug-resistance mutations.