## 2 Chemistry and Structure-Activity Relationship of Styrylquinolines _in vitro_
### Discovery of the 8-hydroxy-quinoline-7-carboxylic acid- pharmacophore  
In line with the initial proposal that a metal ion chelator might act as integrase inhibitor, 8-hydroxyquinoline derivatives were screened in both 3'-processing and strand-transfer assays. However, a complete lack of inhibitory potency was observed with the parent 8-hydroxyquinoline (**2a**) or 8-hydroxyquinaldine (**2b**) and with their \(O\)-alkylated and \(O\)-acylated derivatives. Modulation of the quinoline ring was therefore undertaken taking advantage of the 8-hydroxyl group. **Scheme 1. ** Synthesis of various quinoline and quinaldine derivatives. Kolbe-Schmitt carbonatation according to a previously reported procedure provided acids **2a, 2b** in 20-30% yields (Scheme 1) [15]. Latter on, an improved 60% yield of **2b** was obtained according to a modified protocol in which the potassium phenoxide, formed in anhydrous condition, was treated at 125 \({}^{\circ}\)C under 4 bar of carbon dioxide [16]. Functionalization of the C-2 methyl group required protection of the salicylic moiety. Thus, chemoselective methylation of the carboxylic group was achieved by alkylation using methyl iodide and potassium bicarbonate as base [17]. After protection of the C-8 phenol group as a pivalate ester, selenious anhydride oxidation in pyridine of the fully protected quinaldine **6** and acidic deprotection yielded diacid **7**[18]. Chlorosulfonylation of the C-5 position using neat chlorosulfonic acid at room temperature followed by condensation with morpholine provided the C-5 sulphonamide **4** in 50% yield [19]. Amidification reaction of the C-7 carboxyl group was quite challenging in this series. For example, DMAP/DCC-catalyzed condensation of **3b** with 4-fluorobenzylamine delivered **5** in only 26% yield [20]. After many unsuccessful attempts, it was finally found that carboxyl activation using _N,N_-carbonyl diimidazole followed by primary amine addition gave an improved 60% yield of quinolinecarboxamide **5**[19]. Looking for alternative scaffolds, [PERSON] _et al_. prepared the quinaldine **10** in which the salicylic moiety was shifted to the opposite side of the quinoline ring using Doebner-Miller condensation of 4-aminosalicylic acid with crotonaldehyde. Furthermore, [PERSON] studied the introduction of a nitro group at C-7 instead of the carboxylic acid. Direct sulfonation of 8-hydroxyquinoline (**2a**) gave **11** which was further reacted with sulfonitrile acid to yield the 8-hydroxy-7-nitro-quinadine-5-sulfonic acid (**12**) (Scheme 1) [21]. The biological evaluation of these simple quinoline derivatives on both 3'-processing and strand transfer reactions is depicted in Table 1. Thus, 8-hydroxyquinaldine (**2b**) was found inactive. Adding a carboxylic acid group at C-7 (**3a,b**) did not improve the inhibitory potency of the quinoline scaffold. Nevertheless a promising observation was made in this series: quinaldine **4** bearing a salicylic function at C-7, C-8 and a sulphonamide at C-5 exhibited a low but undeniable activity [19]. Replacement of the carboxyl by another strong electro-withdrawing group such as a nitro group (compound **12**) suppressed completely the activity [21]. When the salicylic system was moved from the C-7, C-8 position to the C-5, C-6 as in **10**, a discrete but significant activity was observed making this compound a promising scaffold [21]. Amide **5** derived from 8-hydroxyquinaldine (**2b**) was found completely devoid of activity. This result was in strong contrast with the Merck finding that 8-hydroxyquinoline and 7-carboxamide[1,6]naphthyridin-8-ols such as **13** and **14**, substituted at C-7 with a large lipophilic residue greatly inhibited strand-transfer [22,23]. Thus, despite their similarity, the 2-substituted quinoline derivatives behaved differently than the unsubstituted parent compounds. The origin of this dichotomy is not clear. As a hypothesis, it may be assumed that two different orientations of the oxine in the enzyme core coexist.