## 2 Chemistry and Structure-Activity Relationship of Styrylquinolines _in vitro_
### Functionalization of the C-5 quinoline position  
Given the positive influence of a polar group at the C-7 position of the quinoline ring on the anti-integrase potency the introduction of an additional group at the C-5 position was studied. 5,7-Dihalostyrylquinolines **60** and **61** (Table 5) were easily prepared through Perkin condensation of the commercially available 5,7-dihalo-8-hydroxyquinaldines with aldehyde **16**[26]. New structural variants possessing an additional carboxyl group at the C-5 carbon atom, either directly bound to the quinoline ring or through an ethylenic spacer were also prepared. The synthesis of 5,7-quinaldinedicarboxylic acid (**69**) took at profit the palladium catalyzed alkoxycarbonylation reaction of 7-iodo-quinaldine **67** which is available in two steps from **66**. Perkin-type condensation of **69** with 3,4-dihydroxy-5-methoxybenzaldehyde and hydrolysis gave the diacid **63** in 21% overall yield. Heck reaction of bromoquinaldine **70** with methyl acrylate afforded unsaturated ester **71** which was next engaged into Perkin condensation with **16** and hydrolysis to provide the 5-propenoic acid derivative **64** in 32% overall yield [34]. \begin{table}
\begin{tabular}{c c c c} \hline \hline \multirow{2}{*}{**R**} & **3\({}^{\star}\)-Processing** & **Strand Transfer** & **References** \\  & **IC\({}_{\text{50}}\) (\(\upmu\)M)** & **IC\({}_{\text{50}}\) (\(\upmu\)M)** & \\ \hline
**59a**, R = H & 82.0 & Untested & 30 \\
**59b**, R = Ph & 50.0\({}^{\text{a}}\) & Untested & 33 \\
**59c**, R = 1-Naphthyl & 92.0 & Untested & 33 \\
**59d\({}^{\text{a}}\)**, R = CH\({}_{3}\) & 0.2 & 0.2 & 34 \\
**59e**, R = C\({}_{\text{S}}\)H\({}_{17}\) & \textgreater{}100.0 \({}^{\text{b}}\) & Untested & 33 \\
**59f**, R = PhCH\({}_{2}\)CH\({}_{2}\) & \textgreater{}100.0 \({}^{\text{a}}\) & Untested & 33 \\
**59g**, R = 4-NO\({}_{2}\)Ph & 100.0 & \textgreater{}100.0 & 33 \\
**59h**, R = 2-NO\({}_{2}\)Ph & \textgreater{}100.0 & 70.0 & 33 \\
**59i**, R = 3,4-F\({}_{2}\)Ph- & 24.0 & \textgreater{}100.0 & 33 \\
**59j**, R = 4-pyridyl & \textgreater{}100.0 \({}^{\text{a}}\) & Untested & 33 \\
**59k**, R = 3-pyridyl & \textgreater{}100.0 & \textgreater{}100.0 & 33 \\
**59l**, R = 2-OH-Ph & \textgreater{}100.0 & \textgreater{}100.0 & 33 \\
**5m**, R = 4-OH-Ph & 65.0 & \textgreater{}100.0 & 33 \\
**59n**, R = 4-(HO\({}_{2}\)C)Ph & 0.2 & Untested & 33 \\
**59o**, R = 3-(HO\({}_{2}\)C)Ph & 0.2 & Untested & 33 \\
**59p**, R = 2-(HO\({}_{2}\)C)Ph & 0.3 & Untested & 33 \\ \hline \hline \end{tabular}  
* 1,3,4-trihydroxyphenyl instead of the 3,4-dihydroxyphenyl ancillary ring. \({}^{\text{b}}\) Overall binding assay.  
\end{table} 
Table 4: _In vitro_ integrase inhibition activities of the 7-aroyl-styrylquinolines derivatives. The 7-arylstyrylquinoline **65** was obtained in 22% overall yield using Suzuki cross-coupling of 4-methoxyboronic acid with 5,7-dibromostyrylquinoline **72**. The remarkable regioselectivity may have its origin in the low reactivity of the C-7 bromine atom in the oxidative addition step due to the presence of a vicinal methoxy group. Lithium bromine exchange reaction, followed by carbon dioxide condensation with the resulting 7-lithio derivative afforded after HBr deprotection the 5-aryl-styrylquinoline **65** (Scheme 8) [19]. Assuming that a sulfonamide group may engage a H-bonding network as a carboxylic acid, [PERSON] _et al._ synthetized a series of 2-styrylquinoline-7-sulfonamides exemplified by **76**, starting from the 7-chloro-8-hydroxyquinaldine (**74**), according to a four-step sequence involving chlorosulfonation, amination, Perkin-type condensation with 3,4-dihydroxybenzaldehyde (**16**) and hydrolysis [36]. **Scheme 8. ** Synthesis of 5-arylstyrylquinoline derivatives **60** and **61** were found to be either inactive or poorly active. On the other hand, bromoacid **62**, which displays a carboxyl group a C-7, showed roughly the same activity that the unsubstitued C-5 derivative **35**.