Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors

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• 作者：Birgit Viira^a ; ^&dagger ; ; Anastasia Selyutina^b ; ^&dagger ; ; Alfonso T. Garcí ; a-Sosa^a ; ^&dagger ; ; Maarit Karonen^c ; Jari Sinkkonen^c ; Andres Merits^b ; ^{andres.merits@ut.ee" class="auth_mail" title="E-mail the corresponding author} ; Uko Maran^a ; ^{uko.maran@ut.ee" class="auth_mail" title="E-mail the corresponding author}
• 关键词：GRASEDUEZOXYIL-UHFFFAOYSA-N ; ZAOAABYOMVFNLJ-UHFFFAOYSA-O ; POXQZKPYJBJIJC-UHFFFAOYSA-N ; IRUKRJUZAAWSSN-UHFFFAOYSA-N ; JOMIDJIZALJVIQ-UHFFFAOYSA-N
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 June 2016
• 年：2016
• 卷：24
• 期：11
• 页码：2519-2529
• 全文大小：1347 K

文摘

A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC₅₀ of 5.6 ± 1.1 μM and 0.16 ± 0.05 μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency.