El-Brollosy N R, Loddo R
Faculty of Science, Heterocyclic Research Unit, Department of Chemistry, Tanta University, Tanta, Egypt.
Dipartimento di Scienze Biomediche, Sezione di Microbiologia e Virologia, Università di Cagliari, Cittadella Universitaria, Monserrato (Cagliari), Italy.
Drug Res (Stuttg). 2016 Apr;66(4):181-8. doi: 10.1055/s-0035-1559683. Epub 2015 Aug 27.
Novel emivirine analogues 6a, b were synthesized by reacting chloromethyl ethyl ether with 5-ethyl/isopropyl-6-(3,5-dimethoxybenzyl)uracils 5e, f. On the other hand, A series of new TNK-651 analogues 10a-f substituted at N-1 with phenoxyethoxymethyl moiety was prepared on treatment of the corresponding uracils 5a-f with bis(phenoxyethoxy)methane (9). The newly synthesized non-nucleosides were tested for antiviral activity against wild type HIV-1 IIIB as well as the resistant strains N119 (Y181C), A17 (K103N+Y181C), and the triple mutant EFV(R) (K103R+V179D+P225H) in MT-4 cells. Most of the tested compounds showed good activities. Among them 6-(3,5-dimethylbenzyl)-5-ethyl-1-[(2-phenoxyethyl)oxymethyl]uracil (10c) and 6-(3,5-dimethylbenzyl)-5-isopropyl-1-[(2-phenoxyethyl)oxymethyl]uracil (10d) that showed inhibitory potency higher than emivirine against both wild type HIV-1 and the tested mutant strains, as well as higher activity than efavirenz against EFV(R).
通过氯甲基乙醚与5-乙基/异丙基-6-(3,5-二甲氧基苄基)尿嘧啶5e、f反应合成了新型依米韦仑类似物6a、b。另一方面，通过用双(苯氧基乙氧基)甲烷(9)处理相应的尿嘧啶5a-f，制备了一系列在N-1位被苯氧基乙氧基甲基部分取代的新型TNK-651类似物10a-f。对新合成的非核苷在MT-4细胞中针对野生型HIV-1 IIIB以及耐药菌株N119(Y181C)、A17(K103N+Y181C)和三重突变体EFV(R)(K103R+V179D+P225H)进行了抗病毒活性测试。大多数测试化合物显示出良好的活性。其中，6-(3,5-二甲基苄基)-5-乙基-1-[(2-苯氧基乙基)氧甲基]尿嘧啶(10c)和6-(3,5-二甲基苄基)-5-异丙基-1-[(2-苯氧基乙基)氧甲基]尿嘧啶(10d)对野生型HIV-1和测试突变菌株均显示出高于依米韦仑的抑制效力，并且对EFV(R)显示出高于依非韦伦的活性。
