Two analogues of the nonnucleoside inhibitor of HIV-1 RT, MKC-442 (emivirine), containing different C6 substituents have been designed to be less susceptible to the commonly found drug-resistance mutation of Tyr181Cys. Compound 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 residue Trp229. Both compounds showed approximately 30-fold greater inhibitory effect than MKC-442 to the Tyr181Cys mutant virus as well as to the clinically important Lys103Asn virus. X-ray crystallographic structure determination of complexes with HIV-1 RT confirmed the predicted binding modes. These strategies might be used to improve the resilience of other NNRTI series against common drug-resistance mutations.

中文翻译：

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MKC-442（emivirine）类似物的设计具有改善的抗药性HIV突变体的活性。

HIV-1 RT的非核苷抑制剂的两个类似物MKC-442（emivirine）含有不同的C6取代基，它们被设计为对Tyr181Cys的常见耐药性突变较不敏感。化合物TNK-6123具有一个C6硫代环己基，旨在更灵活地适应突变的药物结合位点。GCA-186具有额外的3'，5'-二甲基取代基，旨在与保守残基Trp229形成紧密接触。这两种化合物对Tyr181Cys突变病毒以及对临床上很重要的Lys103Asn病毒的抑制作用都比MKC-442大约30倍。X射线晶体结构与HIV-1 RT配合物的测定证实了预测的结合方式。