Norikazu Sakakibara1, Gianfranco Balboni2, Cenzo Congiu2, Valentina Onnis2, Yosuke Demizu3, Takashi Misawa3, Masaaki Kurihara3, Yoshihisa Kato4, Tokumi Maruyama4, Masaaki Toyama5, Mika Okamoto5, Masanori Baba5. 1. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Kagawa, Japan bara@kph.bunri-u.ac.jp. 2. Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy. 3. Division of Organic Chemistry, National Institute of Health Sciences, Setagaya, Tokyo, Japan. 4. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Kagawa, Japan. 5. Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Abstract
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.
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.
Authors: H Tanaka; M Baba; S Saito; T Miyasaka; H Takashima; K Sekiya; M Ubasawa; I Nitta; R T Walker; H Nakashima Journal: J Med Chem Date: 1991-04 Impact factor: 7.446
Authors: A L Hopkins; J Ren; R M Esnouf; B E Willcox; E Y Jones; C Ross; T Miyasaka; R T Walker; H Tanaka; D K Stammers; D I Stuart Journal: J Med Chem Date: 1996-04-12 Impact factor: 7.446