Reaction of the optically active ethyl piperidine-3-carboxylates 4, 5 with formaldehyde and formic acid in methanol at reflux for 6 h afforded the corresponding derivatives 7, 8 in yields of 95.6% and 93.4%, respectively. Chiral piperidine-3-carboxylic acids 1, 2 and piperidine-4-carboxylic acid 3 were reacted with (Boc) 2O in the presence of NaHCO 3 to obtain Boc-protected amine derivatives 9–11 in excellent yields (92.5–97.3%). All starting materials are commercially available. The syntheses of substituted piperidine carboxylic acids 9–14 are shown in Scheme 1. In addition, the effect of P2’-ligands incorporating functionalized 4-substituted phenylsulfonamides on HIV-1 protease inhibitory activity was investigated ( Fig 2). In view of the above phenomena, piperidine-a flexible heterocycle containing exposed nitrogen atom-was introduced as the P2-ligand in the newly designed HIV-1 PIs, with the aim of promoting extensive hydrogen bonding interactions or favorable van der Waals interactions with the backbone atoms in the corresponding S2 Appendix-subsite of PR.
However, the oxygen atom of morpholine in the P2-ligand formed weak van der Waals interaction with the backbone atoms, while the wrapped nitrogen atom failed to make contact with the active site, which might be amenable for the suboptimal activity. The molecular docking of compound A revealed that the small hydrophobic cyclopropyl group filled in the pocket of the S1 Appendix-subsite subtly. Among which, compounds A and B in Fig 1 showed IC 50 values of 53 nM and 47 nM, respectively.
WADE HAAK HOWARD SD SERIES
Recently, we reported a series of PIs incorporating a cyclopropyl as the P1’-ligand and morpholine derivatives as the P2-ligands. 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 of HIV-1 protease (PR). So the design of potent PIs continues to be essential for long-term control of HIV-1 infection and AIDS. 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. Fortunately, 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.
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. 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.
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