## 3 Physico-Chemical Rational of the Styrylquinoline-Integrase Interaction  
### Magnesium binding ability of styrylquinoline integrase inhibitors  
Integrase is a 32-kDa protein that consists of three functional domains. The three domains are necessary for all IN activities except the disintegration, an apparent reverse reaction of the strand transfer [38], for which the catalytic core alone or truncated IN are catalytically competent. The core domain and the C-terminal domain display a DNA-binding activity and are therefore potential targets for SQLs. However, early studies have shown that the core domain-mediated disintegration reaction was efficiently inhibited by SQL compounds, with IC50 values similar to those characterizing the 3'-processing reaction, demonstrating that the SQL binding site is within the central domain of IN [14]. \begin{table}
\begin{tabular}{c c c c} \hline \hline \begin{tabular}{c} HO\({}_{2}\)C \\ \end{tabular} & \begin{tabular}{c} **N\({}^{\prime}\)** \\ \end{tabular} & \begin{tabular}{c} **\(\mathbf{M}\)** \\ \end{tabular} & \
\begin{tabular}{c} **\(\mathbf{M}\)** \\ \end{tabular} &
\begin{tabular}{c} **Reference** \\ \end{tabular} \\ \hline
**Compd nb.** & \(\mathbf{X}\) & \begin{tabular}{c} **3’-Processing** \\ \end{tabular} & \begin{tabular}{c} **Strand Transfer** \\ \end{tabular} \\  & \
\begin{tabular}{c} **IC\({}_{\mathbf{50}}\) (\(\mathbf{\mu}\)M)** \\ \end{tabular} &
\begin{tabular}{c} **IC\({}_{\mathbf{50}}\) (\(\mathbf{\mu}\)M)** \\ \end{tabular} \\ \hline
**35** & HC=CH & 2.4 & 1.0 & 14 \\
**78** & H\({}_{2}\)CCH\({}_{2}\) & 2.3 & 1.5 & 26 \\
**92** & CONH & 0.9 & untested & 18 \\
**93** & CONHCH\({}_{2}\) & 5.0 & & 18 \\
**94** & HNCONHCH\({}_{2}\) & \(>\)100.0 & & 18 \\
**95** & HNCONH & \(>\)100.0 & & 18 \\ \hline \hline \end{tabular}
\end{table} 
Table 8: HIV-1 IN inhibitory potency of spacer modified inhibitors. \begin{table}
\begin{tabular}{c c c} \hline \hline \begin{tabular}{c} HO\({}_{2}\)C \\ \end{tabular} & \begin{tabular}{c} **N\({}^{\prime}\)** \\ \end{tabular} & \
\begin{tabular}{c} **\(\mathbf{R}\)** \\ \end{tabular} &
\begin{tabular}{c} **_In vitro_ biological activity** \\ \end{tabular} \\ \hline
**Compd.** & \(\mathbf{R}\) & \
\begin{tabular}{c} **3’-Processing,** \\ \end{tabular} &
\begin{tabular}{c} **3’-Processing activity of** \\ **the corresponding SQL** \\ **IC\({}_{\mathbf{50}}\) (\(\mathbf{\mu}\)M)** \\ \end{tabular} \\ \hline
**96** & \begin{tabular}{c} \(\mathbf{H}\)**,** \\ \end{tabular} & \begin{tabular}{c} **\(\mathbf{0}\)**,** \\ \end{tabular} & \
\begin{tabular}{c} **6.5** \\ \end{tabular} &
\begin{tabular}{c} 0.7 (\(\mathbf{7}\)**u)** \\ \end{tabular} \\
**97** & \begin{tabular}{c} \(\mathbf{H}\)**,** \\ \end{tabular} & \begin{tabular}{c} \(\mathbf{0}\)**,** \\ \end{tabular} & \
\begin{tabular}{c} 5.0 \\ \end{tabular} &
\begin{tabular}{c} 0.6 (\(\mathbf{7}\)**7n)** \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table} 
Table 9: HIV-1 IN inhibitory potency of spacer modified inhibitors. As hypothesized for the early development of SQLs, one possible mechanism of action is that they block the polynucleotide binding and catalytic site of HIV-1 IN through functional sequestration of the Mg\({}^{2+}\) cofactor by either by the oxine moiety or by their salicylic acid part [26]. With the aim to reinforce this hypothesis, the complexing ability of SQLs for magnesium ions was verified through further experiments including the elaboration and crystallographic characterization of SQL-divalent metal complexes [39]. Unfortunately, attempts to solve the crystal structure of a variety of Mg\({}^{2+}\) complexes of styrylquinolines were unsuccessful. Therefore, complexation of **3b** (Figure 4) by Mg\({}^{2+}\) ion was thus investigated, bearing in mind that previous structure-activity relationship studies [14, 26]. and docking procedures [40, 41, 42]. have identified the salicylic acid moiety of the quinoline half of SQLs as a critical pharmacophore for antiviral activity.