Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors |
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| Affiliation: | 1. Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China;2. College of Pharmacy, Yanbian University, Yanji 133000, People’s Republic of China;3. Institute of Biomedical Science, Fudan University, Shanghai 200433, People’s Republic of China;4. Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, PR China;2. Department of Pharmacology, School of Medicine, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, PR China;3. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;1. Divisione Clinicizzata di Malattie Infettive, Dipartimento di Scienze Biomediche e Cliniche ‘Luigi Sacco'', Universita’ degli Studi di Milano, Milano;2. ITB-CNR, Segrate;3. Malattie Infettive & Microbiologia, Universita’ degli Studi di Genova, Genova;4. Istituto di Microbiologia & Virologia, Universita’ degli Studi di Siena, Siena;5. Istituto di Microbiologia and Virologia, Ospedali Riuniti di Bergamo, Bergamo;6. Istituto di Virologia, Università degli Studi di Bari, Bari;7. Istituto di Virologia, Istituto Scientifico San Raffaele, Milano;8. Virologia, Policlinico Universitario, Modena;9. Clinica Malattie Infettive, Università degli Studi di Bari, Bari;10. Clinica Malattie Infettive, Istituto Scientifico San Raffaele, Milano;11. Immunologia Clinica e Tipizzazione Tessutale, Università Politecnica delle Marche, Torrette di Ancona;12. Malattie Infettive, Ospedale Pediatrico Meyer, Firenze;13. Istituto di Virologia, Ospedale Santo Spirito, Pescara, Italy;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, PR China;2. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium;1. Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan 430205, China;2. School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, China;3. KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium;1. Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, China;2. School of Chemistry & Environmental Engineering, Wuhan Institute of Technology, Wuhan 430073, China;3. KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Ji''nan, 250012, China;2. China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji''nan, 250012, China;3. Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium |
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| Abstract: | A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 μM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 μM. The preliminary structure–activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated. |
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| Keywords: | HIV-1 NNRTIs Diarylpyrimidine SAR Antiviral activity |
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