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A Triazinone Derivative Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity.

A Triazinone Derivative Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity.
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Urano E, Miyauchi K, Kojima Y, Hamatake M, Ablan SD, Fudo S, Freed EO, Hoshino T, Komano J,


Urano E, Miyauchi K, Kojima Y, Hamatake M, Ablan SD, Fudo S, Freed EO, Hoshino T, Komano J, (click to view)

Urano E, Miyauchi K, Kojima Y, Hamatake M, Ablan SD, Fudo S, Freed EO, Hoshino T, Komano J,

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ChemMedChem 2016 9 16() doi 10.1002/cmdc.201600375

Abstract

A novel HIV-1 inhibitor, 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (compound 1), was identified from a compound library screened for the ability to inhibit HIV-1 replication. EC50 values of compound 1 were found to range from 107.9 to 145.4 nm against primary HIV-1 clinical isolates. In in vitro assays, HIV-1 reverse transcriptase (RT) activity was inhibited by compound 1 with an EC50 of 4.3 μm. An assay for resistance to compound 1 selected a variant of HIV-1 with a RT mutation (RT(L100I) ); this frequently identified mutation confers mild resistance to non-nucleoside RT inhibitors (NNRTIs). A recombinant HIV-1 bearing RT(L100I) exhibited a 41-fold greater resistance to compound 1 than the wild-type virus. Compound 1 was also effective against HIV-1 with RT(K103N) , one of the major mutations that confers substantial resistance to NNRTIs. Computer-assisted docking simulations indicated that compound 1 binds to the RT NNRTI binding pocket in a manner similar to that of efavirenz; however, the putative compound 1 binding site is located further from RT(K103) than that of efavirenz. Compound 1 is a novel NNRTI with a unique drug-resistance profile.

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