Design, synthesis and structure-activity studies of rhodanine derivatives as HIV-1 integrase inhibitors

Abstract

Raltegravir was the first HIV-1 integrase inhibitor that gained FDA approval for use in the treatment of HIV-1 infection. Because of the emergence of IN inhibitor-resistant viral strains, there is a need to identify innovative second-generation IN inhibitors. Previously, we identified 2-thioxo-4-thiazolidinone (rhodanine)-containing compounds as IN inhibitors. Herein, we report the design, synthesis and docking studies of a series of novel rhodanine derivatives as IN inhibitors. All these compounds were further tested against human apurinic/apyrimidinic endonuclease 1 (APE1) to determine their selectivity. Two compounds showed significant cytotoxicity in a panel of human cancer cell lines. Taken together, our results show that rhodanines are a promising class of compounds for developing drugs with antiviral and anticancer properties.

Figure 1

Design of new rhodanine derivatives and structural modifications for SAR study.

Figure 2

Structures of representative rhodanine derivatives with diverse biological activities [17,18,19,20]; (2) JSP-1 inhibitor; (3) PDE4 inhibitor; (4) HCV NS3 Protease inhibitor; (5) Antitumor agent (rhodanine moiety is highlighted in red).

Scheme 1

Synthesis of compounds 6–54.

Figure 3

(A) A representative gel showing inhibition of purified IN by selected compounds. Lanes 1: DNA alone; Lanes 2 and 15: DNA and IN alone with no drug; Lanes 3–14: DNA with IN and selected drug concentrations (lanes: 3–6: compound 48; lanes 7–10: compound 53; lanes 11–14: compound 51; at concentrations: 100, 33.3, 11.1 and 3.7 μM); (B) A representative gel showing inhibition of purified APE1 by selected compounds. Lanes 1: DNA alone; Lanes 2 and 15: DNA and APE1 alone with no drug; Lanes 3–26: DNA with APE1 and selected drug concentrations (lanes: 3–6: compound 48; lanes 7–10: compound 53; lanes 11–14: compound 51; lanes 15–18: compound 9; lanes 19–22: compound 7; lanes 23–26: compound 8; at concentrations: 100, 33.3, 11.1 and 3.7 μM).

Figure 4

Plot of pIC₅₀ (IN ST activity) versus the predicted Glide docking score.

Figure 5

The proposed binding modes of (a) compound 11, and (b) compound 6–8 in the HIV-1 IN active site. Close contact residues are shown as green sticks. Compounds 11 and 6–8 are shown in pink (colored by atom types) and Mg²⁺ is shown in red.

Figure 6

The proposed binding modes of (a) compound 39; (b) compound 53; and (c) compound 54 in the HIV-1 IN active site. Close contact residues are shown as green sticks. Compounds 39, 53, and 54 are shown in pink (colored by atom types) and Mg²⁺ is shown in red.