(±)-7-Isopropoxy-8-(naphth-1-yl)quinoline (B#24) was recently identified as a low micromolar inhibitor of HIV-1, specifically its RNase H activity. However, whether or not the enantiomeric atropisomers of this azaBINOL derivative are configurationally stable, and, if so, how the absolute configuration of B#24 affects its biological activity, are issues yet to be addressed. It is here reported that the atropisomers of B#24 can be resolved by standard chiral stationary phase preparative HPLC and that the separated optical isomers retain their stereochemical integrity indefinitely at ambient conditions in the pure state (i.e., no change in %ee during ≥14 d at rt). Furthermore, it has been established that (+)-B#24 is 3-6 times more potent in its inhibition of HIV-1 in a single round HIV-1 infectivity assay as compared to its antipode (–)-B#24. These new findings will be presented in detail alongside the results of ongoing work to optimize the synthesis and resolution of B#24, to assign absolute configurations to its optical isomers, and to fully explore its enantiomerization kinetics via Eyring plot analysis. Knowledge of the parameters studied will aid future efforts to use B#24 as a lead compound en route to superior agents for HIV-1 neutralization.

Synthesis, resolution, and configurational stability of 7-isopropoxy-8-(naphth-1-yl)quinoline and the influence of its absolute configuration on effectiveness of HIV-1 neutralization

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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