Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 16; p. 127287
• Main Authors: Sun, Songkai, Huang, Boshi, Li, Zhuo, Wang, Zhao, Sun, Lin, Gao, Ping, Kang, Dongwei, Chen, Chin-Ho, Lee, Kuo-Hsiung, Daelemans, Dirk, De Clercq, Erik, Pannecouque, Christophe, Zhan, Peng, Liu, Xinyong
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15-08-2020
• Subjects: Anti-HIV activity; Dual-target prodrug; HIV-1; Metabolic stability; NCp7; HIV-1; NCp7; Anti-HIV activity; RT; Metabolic stability; Dual-target prodrug
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127287

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•Dual-target prodrug of HIV-1 reverse transcriptase inhibitor and NCp7 inhibitor.•Dual target prodrug modification improves antiviral activity and selectivity index.•The compound releases parent drugs linearly in the plasma, with prodrug properties.
In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole (EC50 = 0.308 μM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC50 = 1.329 μM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.