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. 2012 May 24;55(10):4764-75.
doi: 10.1021/jm3002247. Epub 2012 May 10.

Design, synthesis, and antiviral activity of entry inhibitors that target the CD4-binding site of HIV-1

Francesca Curreli  1 , Spreeha Choudhury, Ilya Pyatkin, Victor P Zagorodnikov, Anna Khulianova Bulay, Andrea Altieri, Young Do Kwon, Peter D Kwong, Asim K Debnath
Affiliations

Design, synthesis, and antiviral activity of entry inhibitors that target the CD4-binding site of HIV-1

Francesca Curreli et al. J Med Chem. .

Abstract

The CD4 binding site on HIV-1 gp120 has been validated as a drug target to prevent HIV-1 entry to cells. Previously, we identified two small molecule inhibitors consisting of a 2,2,6,6-tetramethylpiperidine ring linked by an oxalamide to a p-halide-substituted phenyl group, which target this site, specifically, a cavity termed "Phe43 cavity". Here we use synthetic chemistry, functional assessment, and structure-based analysis to explore variants of each region of these inhibitors for improved antiviral properties. Alterations of the phenyl group and of the oxalamide linker indicated that these regions were close to optimal in the original lead compounds. Design of a series of compounds, where the tetramethylpiperidine ring was replaced with new scaffolds, led to improved antiviral activity. These new scaffolds provide insight into the surface chemistry at the entrance of the cavity and offer additional opportunities by which to optimize further these potential-next-generation therapeutics and microbicides against HIV-1.

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Figures

Figure-1
Figure-1
Structure of 1 and 2 identifying different pharmacophoric regions.
Figure-2
Figure-2
GLIDE-based docking of compound 6 in the “Phe43 cavity”. (a) Compound 6 is shown as docked inside the cavity. The 4-chlorophenyl moiety is located deep inside the cavity. The protonated “N” of piperidine ring is within salt-bridge (H-bond interaction) distance from Asp368; (b) the interactions of 6 with the residues in the “Phe43 cavity” of HIV-1 gp120 as mapped by the Maestro software in Schrödinger Suit 2011.
Figure-3
Figure-3
Binding mode of two of the most active compounds, 27 and 39. (a & b), the docking-based top scored two conformations of 27 showed distinct differences in binding of the piperidine-thiazolyl moiety. The piperidine NH formed an H-bond/salt-bridge with Asp368 in the second best scored conformation but not in the top scored conformation. (c & d) Both top scored two conformations of 39, on the other hand, formed the H-bond/salt-bridge with Asp368. However, the ethanol moiety in the thiazolyl ring showed two distinct binding modes. The symbol notations are same as in Figure-2.
Scheme-1
Scheme-1
a. CICOCOOEt, NEt3, DCM; b. NaOH, EtOH, H2O, c. TBTU, NEt3, amine, d. HCI/Dioxane (this step is only required to deproted N-Boc amines)
Scheme-2
Scheme-2
a. CICOCOOEt, NEt3, DCM; b. NaOH, EtOH, H2O, c. TBTU, NEt3, amine, d. HCI/Dioxane
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