Structure−Activity Relationships and Binding Mode of Styrylquinolines as Potent Inhibitors of HIV-1 Integrase and Replication of HIV-1 in Cell Culture

Abstract

Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.

Investigation of the Binding Affinity between Styrylquinoline Inhibitors and HIV Integrase Using Calculated Nuclear Quadrupole Coupling Constant (NQCC) Parameters (A Theoretical ab initio Study)

“…As shown in docking results, the oxygen atoms of carboxyl group and hydroxyl group may coordinate with Mg +2 ion within the enzyme catalytic site. 39 This docking mode was the same as the experiment report given by zouhiri et al 34 Thus, based on previous studies the oxygen atoms of carboxyl group and hydroxyl group in styrylquinolines have dominant role in drug activity regardless of determining the active sites.…”

“…Some previous researches 34 indicate that the presence of a 7-carboxyl-8-hydroxyl patterns in the quinoline half and an aromatic or heteroaromatic ancillary subunit is required for the biological activity of styrylquinoline (Figure 1).…”

“…In other words the compounds 20 and 21 can be roughly classified as active and 28 as inactive derivatives of styrylquinoline. 34 The calculated NQCCs of oxygen atoms of hydroxyl group and carboxyl group of these compounds were listed in Table 1.…”

Drug Design by Regression Analyses of Newly Synthesized Derivatives of 8-Quinolinol

“…The antibacterial activity of 8-hydroxyquinoline and its derivatives is long-known. The drugs from this group are used as chemotherapeutics in medicine for more than 120 years (9,10,11,21), and in analytical chemistry as chelators (8,12). In previous studies of ours, some newly synthesized derivatives of 8-Quinolinol were shown to exhibit a higher microbiological activity (4,5,15).…”

“…The Quantitative Structure Activity Relationship (QSAR) approach is widely used to look for and predict new compounds with high biological activity. The evaluation of the bioactivity of such compounds through their physical, chemical and physicochemical traits is most commonly performed with regression equations of the structure-activity type using regression analysis (6,7,14,21). The purpose of this method is to derive empirical relations between various sets of chemical, physical or structural parameters and the biological activity of compounds.…”