HIV-1 reverse transcriptase（RT） inhibitors are major components of HAART（highly active antiviral therapy）. The S-DABOs（dihydro-alkylthio-benzyl-oxopyrimidines） series and their similar skeletons have exhibited preferable activities to inhibit HIV-1 RT. In the present study, we generated field-based QSAR models using common structure alignment, which was characterized by Gaussian steric, electrostatic, hydrophobic, hydrogen bond donor, hydrogen bond acceptor and aromatic ring fields（R2 = 0.8421, RCV2 = 0.5949 for the training set, Q2 = 0.5486, Pearson-r = 0.7460 for the test set）. Docking, pocket surface and contour map analyses were carried out. Key pharmacophore features were investigated, including（i） π-π interaction with residue Tyr181, Tyr188 and Trp229, σ-π interaction with His236,（ii） hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The docking analysis and field-based QSAR models could provide reasonable guidance in the rational design of potent HIV-1 RT inhibitors.
trans-3-Isopropyl-4-（2-methylcyclohexyloxy）-6-phenethylpyridin-2（1H）-one, as reverse transcriptase （NNRTIs）, exhibited significant potent activity not only against wild-type HIV-1 strains but also on mutant strains. For furthering study this compound, the original synthetic route should be shorten to improve the total yield. In this report, we designed an efficient synthetic strategy to obtain the target compound with higher yield.
Among the structurally diverse NNRTIs, pyridinone scaffolds demonstrate high potency against HIV-1 wild type and drug-resistant strains. During the optimization of our pyridinone compound 1（LAM-trans）, we found that the introduction of the N atoms in the C-4 position could dramatically improve the water solubility（7b）, whereas protonation of the piperidine N atom resulted in a decrease in its hydrophobic interaction with the binding pocket. In particular, protonation altered the orientation of the alicyclic rings in the hydrophobic pocket, thus impeding the formation of key halogen bond and eventually leading to a huge change in anti-HIV-1 RT activity. These results provided theoretical and experimental basis for the subsequent structural modification of pyridinone compounds.
Yunqi LiuXixi LiXiaodong DouChao TianZhili ZhangJunyi LiuXiaowei Wang
钴胺素依赖的蛋氨酸合酶催化N5-甲基四氢叶酸转移甲基至同型半胱氨酸生成蛋氨酸和四氢叶酸,直接参与蛋氨酸循环、叶酸循环及含硫氨基酸代谢,与DNA、蛋白质合成及生物甲基化有密切关系。本研究采用蛋白层析技术,将大鼠肝匀浆经超声破碎和高速离心处理后,依次经过DE-52批处理、Q Sepharose Fast Flow离子交换层析和CHT陶瓷羟基磷灰石吸附柱层析进行纯化,并对纯化产物进行了SDS-PAGE和Western blotting鉴定。采用分光光度法测定蛋氨酸合酶的活性,对纯化酶的酶促反应动力学进行了研究,确定了最佳反应条件,动力学结果显示蛋氨酸合酶的双底物酶促反应的机制为乒乓机制。研究表明,采用层析技术纯化得到的蛋氨酸合酶适用于以其为靶点的化合物高通量筛选。
With rapid spread of HIV(human immunodeficiency virus) on a global scale and increasingly severe drug-resistance of it,it is urgently necessary to develop novel effective anti-HIV drugs.Non-nucleoside reverse transcriptase inhibitor(NNRTIs)is one of the most significant antiretroviral drugs for fighting against HIV infection due to their various structures,unique mode of action,good efficacy and low toxicity.Pyridinone derivatives,a type of NNRTIs,have been reported to achieve remarkable development in the past few decades.In this review,we summarized current drug design and medicinal chemistry efforts toward the development of next-generation pyridinones as HIV-1 NNRTIs.
A series of （1E）-phenyl-2-（3＇,4＇-dihydroxyphenyl）ethenesulfonate derivatives were designed and synthesized as anti-amyotrophic lateral sclerosis （ALS） agents, based on the lead compound caffeic acid phenethyl ester （CAPE）. And their neuroprotective activities were evaluated. The results indicated that replacement of the carboxylic ester by sulfonic ester did not produce better neuroprotective activity in the model of LPS induced inflammation in BV2 cells. However, the results in the model of H2O2 induced damage in PC12 cells showed that the neuroprotective activities of all the target compounds and CAPE were about the same.
Thymidylate synthase （TS, E.C.2.1.1.45） catalyzes a critical reaction in the only pathway of de novo synthesis of thymidylate （dTMP） in human cells, and is an important target of chemotherapy. To evaluate the inhibitory activities of novel compounds to TS, a convenient method of activity assay using 6x His-tagged recombinant human TS （rhTS） was established and 49 novel synthetic folate analogues were screened to discover potential TS inhibitors. During the process, 4 novel compounds were found to effectively inhibit TS, while the IC 50 of a positive control raltitrexed was 3.4 μM in this assay.
An effective synthesis method for preparing 4,6-disubstituted pyridinones was reported. Ethyl 3-oxo-4-phenylbutyrate was an important intermediate, by which 6-substituted pyridinones could be prepared. The decarboxylation condition was optimized for compound 4. After protected with a methoxy group, the compound was reacted with BnBr to form the target compound 11. The structures were characterized by ^1H NMR, ^13C NMR and HRMS, and its enzyme inhibition activity was also determined.
A series of novel dihydro-alkylthio-benzyl-oxopyrimidines （S-DABOs） 7a-f have been designed and synthesized with an efficient method. Biological evaluation of their HIV-1 reverse transcriptase inhibitory activities was performed using Nevirapine （NVP） as a reference compound. Among the series, compound 7d shows the highest reverse transcriptase inhibitory activity, which is better than Nevirapine.
