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Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants.

ABSTRACT: Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme K_i of 0.092 nM and 0.21 nM, as well as antiviral IC₅₀ values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94% and 91%, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.

SUBMITTER: Zhu M

PROVIDER: S-EPMC7294734 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants.

Zhu Mei M Dou Yue Y Ma Ling L Dong Biao B Zhang Fan F Zhang Guoning G Wang Juxian J Zhou Jinming J Cen Shan S Wang Yucheng Y

ACS medicinal chemistry letters 20200331 6

Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor <b>23a</b> and carbamido inhibitor <b>27a</b> exhibited almost 4- and 2-fold superior activity with e ...[more]

PMID: 32551001

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