Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure–activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.

人类免疫缺陷病毒（HIV）是获得性免疫缺陷综合症（AIDS）的主要传染源，非核苷逆转录酶抑制剂（NNRTIs）是HIV治疗的基石。在过去的20年中，我们的药物化学小组在开发几种独特的新型NNRTIs方面取得了长足的进步，包括1-[（（2-羟基乙氧基）甲基] -6-（苯硫基）胸腺嘧啶（HEPT），硫代-二氢-烷氧基-苄基-oxopyrimidine（小号-DABO），二芳基三嗪（DATA），二芳基嘧啶（DAPY）类似物及其杂化衍生物。整合的现代医学策略的应用，包括基于结构的药物设计，基于片段的优化，支架/片段跳跃，分子/片段杂交和生物立体异构，导致了几种高效的类似物的开发，可用于进一步评估。在本文中，我们使用上述优化策略回顾了过去二十年中NNRTIs的发展，包括其结构-活性关系，分子模型及其与HIV-1逆转录酶（RT）的结合模式。还讨论了有关设计以及相关挑战的未来方向和观点。