Long-range two-dimensional1H-15N heteronuclear shift correlation at natural abundance using GHNMQC. A study of the reverse transcriptase inhibitor delavirdine

Abstract

Delavirdine is a novel BHAP [bis(heteroaryl)piperazine] RT (reverse transcriptase) inhibitor in the final stages of development for treatment of human AIDS (acquired immuno deficiency syndrome). The assignment of the six unique nitrogen resonances in the molecule and its 5-aminoindole precursor are reported at natural abundance using the two-dimensional GHNMQC (gradient hydrogen–nitrogen multiple quantum coherence) experiment. The molecule contains three protonated secondary nitrogens and three tertiary nitrogens in its structure. The protonated nitrogen of the acidic sulfonamidomethyl moiety at the 5-position of the indole substituent of the molecule is shown to be sufficiently acidic in DMSO solutions at ambient temperature to preclude the observation of a direct response for this 1H–15N heteronuclear pair; in contrast, direct responses for the indole and isopropyl amino nitrogens were readily observable under these conditions. Variable-temperature studies in pyridine demonstrated that it was possible to slow autoprotonation sufficiently to allow the direct response to be observed with full intensity at -35°C. Similar, although less pronounced behavior was observed for the 5-amino group contained in the structure of the 5-aminoindole precursor of delavirdine. The broad proton multiplet for the H-2′/H-6′ methylene proton resonance of the piperazine portion of the molecule failed to afford a direct response to the piperazine N-4′ resonance in the conventional GHNMQC experiment. Modifying the pulse sequence to apply a selective pulse to the H-2′/H-6′ proton in a manner analogous to that recently reported for the selective HMBC experiment readily facilitated the observation of the otherwise absent long-range coupling to N-4′. © 1997 John Wiley & Sons, Ltd.