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Design, Discovery, Modelling, Synthesis, and Biological Evaluation of Novel and Small, Low Toxicity S-Triazine Derivatives as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Design, Discovery, Modelling, Synthesis, and Biological Evaluation of Novel and Small, Low Toxicity S-Triazine Derivatives as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Birgit Viira, Anastasia Selyutina, Alfonso T García-Sosa, Maarit Karonen, Jari Sinkkonen, Andres Merits, Uko Maran

Bioorg Med Chem. 2016 Jun 1;24(11):2519-29.

PMID: 27108399

Abstract:

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±1.1μM and 0.16±0.05μM 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP331261508	HIV inhibitor 18A		331261-50-8	Price

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