Antiviral chemistry & chemotherapy · 2015
Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives.
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Sakakibara Norikazu, Balboni Gianfranco, Congiu Cenzo, Onnis Valentina, Demizu Yosuke, Misawa Takashi, Kurihara Masaaki, Kato Yoshihisa, Maruyama Tokumi, Toyama Masaaki, Okamoto Mika, Baba Masanori
Аннотация
BACKGROUND: The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure-activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors.
METHODS: A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells.
RESULTS: Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 µM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents.
CONCLUSION: The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.
METHODS: A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells.
RESULTS: Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 µM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents.
CONCLUSION: The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.