Biological evaluation of molecules of the azaBINOL class as antiviral agents: Inhibition of HIV-1 RNase H activity by 7-isopropoxy-8-(naphth-1-yl)quinoline

Abstract

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Antiviral Agents – Benzazine Derivatives

“…These results indicate that quinoline 5 is a potential lead compound in the development of new HIV-1 RNase H inhibitors. 7 A wide range of quinoline derivatives 9-11 (Fig. 4) have been studied as novel inhibitors of HIV penetration.…”

Axially chiral phenolic derivatives of 8,8´-biquinolyl and 8-(naphth-1-yl)quinoline as platforms for discovery: The unfolding story of the 'azaBINOLs'

“…The first successful approach to 8,8´-diazaBINOL (3) 2 was based on directed ortho-metallation chemistry and it took advantage of the known propensity of the N,N-dimethyl carbamate derivative of 7-hydroxyquinoline (10) to selectively lithiate at C8 (Scheme 2). 14 With the C8-position activated as a carbanion (organolithium 11), the desired biquinolyl 13 was generated initially by iodination followed by Ullmann-type biaryl coupling of the intermediate 8-iodoquinoline 12.…”

“…In a triage screen, three 8-azaBINOL derivatives were identified from a modestly sized library of azaBINOL compounds to possess promising activity in a pseudo-typed viral particle single-round infectivity assay (HIVpp) at single-dose concentrations: 88, 89, and 91. 10 These compounds, in addition to a set of three close-structural analogs including comparable 8,8´-diazaBINOLs (92 and 93), were further evaluated for their IC 50 values against HIV-1 particles pseudo-typed with HIV-1 envelope proteins originating from three different HIV-1 strains in TZM-bl cells (the data illustrated for the HXB2 isolate are representative), and then in fullyinfectious, replication competent HIV-1 LAI in LC5-RIC cells using the 'EASY-HIT' full viral infection assay system (Table 3). 64 Of the six compounds studied at this level of detail, only the isopropyl ether of 2´-deoxy-8-azaBINOL (88) showed consistent low micromolar IC 50 values against HIV-1 while exhibiting a cytotoxicity to efficacy selectivity index (CC 50 /IC 50 ) in the employed cell types of over 10.…”

“…64 Of the six compounds studied at this level of detail, only the isopropyl ether of 2´-deoxy-8-azaBINOL (88) showed consistent low micromolar IC 50 values against HIV-1 while exhibiting a cytotoxicity to efficacy selectivity index (CC 50 /IC 50 ) in the employed cell types of over 10. 10 It is noteworthy that isosteric changes to the structure of 88, including formally relocating the isopropoxy substituent to the naphthyl-ring (90) and introduction of an additional aromatic-ring bound N-atom (92), result in loss of anti-viral activity. Given the promising in vitro anti-HIV activity discovered for 88, which it was found extended to a multidrug resistant isolate (HIV-1 V13-03413B ) 65 extensive mode-of-action studies were undertaken to identify its molecular target.…”

“…The interested reader is referred to the original azaBINOL publications cited herein for a full exposition of the topics presented with more extensive background literature. [2][3][4][5][6][7][8][9][10] Throughout, atom positions within azaBINOL molecules are referred to in relation to BINOL numbering (see Figure 1); however, the numbering of any quinoline precursors conforms to the usual IUPAC convention.…”