Abstract
A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2’-ligands and a hydrophobic cyclopropyl group as the P1’-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2’-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.
Highlights
HIV-1 infection has become a serious threat to human beings around the world since the first case was reported in 1981 in the USA [1]
An estimated 37.9 million people lived with HIV-1 and 770 thousand people died from AIDS-related diseases in 2018, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS)’s 2019 fact sheet on global HIV & AIDS statistics [2]
HIV-1 protease inhibitors (PIs) serve as a critical therapeutic approach for the treatment of HIV-1 infection due to their ability to block the production of viral proteins for mature virions [4,5,6]
Summary
HIV-1 infection has become a serious threat to human beings around the world since the first case was reported in 1981 in the USA [1]. The emergence of a large variety of antiviral drugs, especially the application of HIV-1 protease inhibitors (PIs) in highly active antiretroviral therapy (HAART), made significant contributions to transforming HIV-1 infection from an inevitably fatal disease into a manageable chronic ailment [3, 4]. HIV-1 PIs serve as a critical therapeutic approach for the treatment of HIV-1 infection due to their ability to block the production of viral proteins for mature virions [4,5,6]. The design of potent PIs continues to be essential for long-term control of HIV-1 infection and AIDS [7,8,9,10]. In an effort to develop structurally novel PIs that exhibit potent inhibitory activity, one of the major design strategies is to optimize ligand-binding site interactions with the active site
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