Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74

PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack information regarding optical purity (enantiomeric excess) single stereogenic centre has resulted in ambiguity as to potency different samples this compound. Herein described synthesis enantiomerically enriched (S)- and (R)-PF74 further enrichment (≥98%) using chiral HPLC resolution. The biological activities each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) be significantly more active than 19 µM). Computational docking studies conducted rationalise large discrepancy activity, indicated binding conformations for enantiomer. energy conformation adopted by (ΔG = −73.8 kcal/mol) was calculated favourable less (R)-enantiomer −55.8 agreement with experimental observations.