Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors.
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.
Institute of Chemistry, University of Tartu, Tartu 50411, Estonia.
Birgit
B
Viira
Institute of Technology, University of Tartu, Tartu 50411, Estonia.
Anastasia
A
Selyutina
Institute of Chemistry, University of Tartu, Tartu 50411, Estonia.
Alfonso T
AT
García-Sosa
Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
Maarit
M
Karonen
Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
Jari
J
Sinkkonen
Institute of Technology, University of Tartu, Tartu 50411, Estonia. Electronic address: andres.merits@ut.ee.
Andres
A
Merits
Institute of Chemistry, University of Tartu, Tartu 50411, Estonia. Electronic address: uko.maran@ut.ee.
Uko
U
Maran
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
Antiviral activity; HIV; Molecular docking; Non-nucleoside reverse transcriptase inhibitors; Synthesis