Roth T, Morningstar M L, Boyer P L, Hughes S H, Buckheit R W, Michejda C J
Molecular Aspects of Drug Design Section, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
J Med Chem. 1997 Dec 19;40(26):4199-207. doi: 10.1021/jm970096g.
The development of new nonnucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) active against the drug-induced mutations in RT continues to be a very important goal of AIDS research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as the lead structure for drug design with the objective of making more potent inhibitors against both wild-type (WT) and variant RTs. A series of structurally related 1,2-substituted benzimidazoles was synthesized and evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT RT. A structure-activity study was carried out for the series of compounds to determine the optimum groups for substitution of the benzimidazole ring at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 = 440 nM) against wild-type virus while retaining broad activity against many clinically observed HIV-1 strains resistant to nonnucleoside inhibitors. Overall, the activity of 35 against wild-type and resistant strains with amino acid substitution in RT is 4-fold or greater than that of TZB and is comparable to that of other nonnucleoside inhibitors currently undergoing clinical trials, most of which do not have the capacity to inhibit the variant forms of the enzyme.
开发对人免疫缺陷病毒1型（HIV-1）逆转录酶（RT）具有活性、能对抗RT中药物诱导突变的新型非核苷类抑制剂，仍然是艾滋病研究的一个非常重要的目标。我们使用一种已知的HIV-1 RT抑制剂1-(2,6-二氟苯基)-1H,3H-噻唑并[3,4-α]苯并咪唑（TZB）作为药物设计的先导结构，目的是制备出对野生型（WT）和变异型RT都更有效的抑制剂。合成了一系列结构相关的1,2-取代苯并咪唑，并评估了它们抑制HIV-1 WT RT体外聚合的能力。对该系列化合物进行了构效关系研究，以确定苯并咪唑环在N1和C2位置取代的最佳基团。最佳抑制剂1-(2,6-二氟苄基)-2-(2,6-二氟苯基)-4-甲基苯并咪唑（35）在体外酶试验中对HIV-1 WT RT的IC50 = 200 nM。利用感染HIV的MT-4细胞进行的细胞保护试验表明，35对野生型病毒具有很强的抗病毒活性（EC50 = 440 nM），同时对许多临床上观察到的对非核苷类抑制剂耐药的HIV-1毒株保持广泛活性。总体而言，35对RT中具有氨基酸取代的野生型和耐药毒株的活性比TZB高4倍或更高，与目前正在进行临床试验的其他非核苷类抑制剂相当，其中大多数没有抑制该酶变异形式的能力。
