Design,synthesis and biological evaluation of novel acetamide-substituted doravirine and its prodrugs as potent HIV-1 NNRTIs |
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Authors: | Zhao Wang Zhao Yu Dongwei Kang Jian Zhang Ye Tian Dirk Daelemans Erik De Clercq Christophe Pannecouque Peng Zhan Xinyong Liu |
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Institution: | 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, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium |
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Abstract: | A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8?nM. Among them, the two most potent compounds 8i (EC50?=?59.5?nM) and 8k (EC50?=?54.8?nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50?=?12.8?μM) and comparable to doravirine (EC50?=?13?nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N?+?Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail. |
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Keywords: | HIV-1 NNRTIs Doravirine Acetamide Prodrug Drug design |
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