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本文评价了5个二甲苯酮类非核苷类逆转录酶抑制剂(DY1203、DY1204、DY1119、DY1208和DY1209)的体外抗HIV-1药效学。采用MTT法检测了5个化合物对人T淋巴细胞系(C8166、MT-4、H9)和PBMC的毒性作用;p24抗原ELISA方法测定了化合物对1株HIV-1实验株、4株耐药株和3株临床株的抗病毒活性;HIV逆转录酶试剂盒检测了化合物体外对HIV-1重组逆转录酶的抑制活性。结果表明,5个化合物中,DY1203和DY1204对不同细胞的毒性均很小(CC50>200μg·m L-1)。DY1119、DY1208和DY1209具有显著的抗病毒活性,对实验株HIV-1IIIB、NRTI耐药株HIV-174V、PI耐药株HIV-1RF/V82F/184V、FI耐药株HIV-1NL4-3 gp41(36G)N42S和临床分离株(HIV-1KM018、HIV-1TC-1、HIV-1Wan)均有很强的抑制作用,而NNRTI耐药株HIV-1A17对其有不同程度耐药。5个化合物对HIV-1重组逆转录酶有不同程度的抑制效应,其中DY1208有显著的抗HIV-1活性和较高的治疗指数,安全性高,有望成为新的抗HIV-1先导化合物。
In this paper, we evaluated the in vitro anti-HIV-1 pharmacodynamics of five xylenol non-nucleoside reverse transcriptase inhibitors (DY1203, DY1204, DY1119, DY1208 and DY1209). The toxicities of 5 compounds to human T lymphocyte cell lines (C8166, MT-4, H9) and PBMCs were tested by MTT assay. The inhibitory effect of the compounds against 1 HIV-1 experimental strain, 4 resistant strains And three clinical strains were tested for their antiviral activity. The HIV reverse transcriptase kit was used to test the inhibitory activity of the compounds against HIV-1 recombinant reverse transcriptase in vitro. The results showed that among the five compounds, DY1203 and DY1204 had little toxicity to different cells (CC50> 200μg · m L-1). DY1119, DY1208 and DY1209 had significant antiviral activity against HIV-1IIIB, NRTI resistant strains HIV-174V, PI resistant strains HIV-1RF / V82F / 184V and FI resistant strains HIV-1NL4-3 gp41 36G) N42S and clinical isolates (HIV-1KM018, HIV-1TC-1 and HIV-1Wan). However, NNRTI resistant strain HIV-1A17 was resistant to some extent. Five compounds have different inhibitory effects on HIV-1 recombinant reverse transcriptase. Among them, DY1208 has significant anti-HIV-1 activity, high therapeutic index and high safety, and is expected to become a new anti-HIV-1 lead compound.