De-novo design, synthesis and evaluation of novel 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as HIV-1 reverse transcriptase inhibitors.
De-novo design, synthesis and evaluation of novel 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as HIV-1 reverse transcriptase inhibitors.
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DOI：
10.1186/s13065-015-0111-6
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发表时间：
2015
影响因子：
--
通讯作者：
Murugesan S
中科院分区：
文献类型：
--
作者：
Chander S;Ashok P;Singh A;Murugesan S
获得性免疫缺陷综合征（AIDS）是由人类免疫缺陷病毒（HIV）引起的感染的晚期。艾滋病毒/艾滋病作为一种疾病和歧视的根源，对社会产生了巨大影响。非核苷类逆转录酶抑制剂（Non-Nucleoside Reverse Transcriptase Inhibitors, NNRTIs）是一类结合HIV逆转录酶（RT）的结构多样的化合物。与其他抗hiv药物一样，由于耐药的迅速发展，已批准的nnrti的长期临床效果受到阻碍。因此，迫切需要发现能有效对抗HIV-1 rt的药敏和耐药菌株的NNRTIs。设计合成了两种新型的30,6,7-二甲氧基-1,2,3,4-四氢异喹啉类似物（5a-o）和（8a-o）作为HIV-1逆转录酶抑制剂。采用红外光谱、质子核磁共振光谱、质谱等方法对合成的化合物进行了表征，并对其体外RT抑制活性进行了评价。在测试的100 μM浓度下，18个化合物的抑制率超过50%，其中化合物8h和8l的抑制率分别为74.82%和72.58%。对测试化合物进行初步构效关系（SAR）分析，并对两种显著活性化合物8h和8l进行对接研究，以验证其与HIV-RT的结合。所合成化合物的预测理化参数均在可接受的药物性能范围内。本研究结果表明，合成的化合物（5a-o）和（8a-o）表现出中等到有希望的HIV-1 RT抑制活性。整体的SAR研究有助于进一步鉴定HIV-1 rt的先导物和设计新的潜在抑制剂。化合物8h在3MEE酶的非核苷抑制结合袋内的最佳对接位。
Acquired Immune Deficiency Syndrome (AIDS) is the advanced stage of infection caused by Human Immunodeficiency Virus (HIV). HIV/AIDS had a great impact on society, both as an illness and as a source of discrimination. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are structurally diverse group of compounds which binds to Reverse Transcriptase (RT) enzyme of HIV. Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. So, there is an urgent need to discover the NNRTIs, which can be effective against the drug sensitive as well as drug resistant strains of HIV-1 RT. Two series of novel thirty, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogues (5a-o) and (8a-o) were designed and synthesized as inhibitor of HIV-1 reverse transcriptase. All the synthesized compounds were characterized by infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectroscopy and evaluated for in-vitro RT inhibitory activity. Among the tested compounds, eighteen compounds exhibited more than 50 % inhibition at tested 100 μM concentration, in which two compounds 8h and 8l showed promising inhibition (74.82 and 72.58 %) respectively. The preliminary structure–activity relationship (SAR) of the test compounds and docking studies of the two significantly active compounds 8h and 8l were performed to examine their putative binding with HIV-RT. Predicted physiochemical parameters of the synthesized compounds were within the acceptable range of drugable properties. The results obtained from this investigation revealed that, the synthesized compounds (5a-o) and (8a-o) showed moderate to promising HIV-1 RT inhibition activity. The overall SAR studies can help in identification of further lead as well as in designing of newer potential inhibitor of HIV-1 RT. Best docked pose of compound 8h inside the non-nucleoside inhibitory binding pocket of 3MEE enzyme.
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影响因子：
120.1
作者：
Flexner, Charles
通讯作者：
Flexner, Charles
admetSAR：用于评估化学 ADMET 特性的综合来源和免费工具
影响因子：
5.6
作者：
Cheng, Feixiong;Li, Weihua;Tang, Yun
通讯作者：
Tang, Yun
影响因子：
7.3
作者：
Friesner, Richard A.;Murphy, Robert B.;Mainz, Daniel T.
通讯作者：
Mainz, Daniel T.
影响因子：
15
作者：
Jorgensen, WL;Maxwell, DS;TiradoRives, J
通讯作者：
TiradoRives, J
影响因子：
3.5
作者：
Kashiwada, Y;Aoshima, A;Lee, KH
通讯作者：
Lee, KH