Exploration of Structure–Activity Relationship of Aromatic Aldehydes Bearing Pyridinylmethoxy-Methyl Esters as Novel Antisickling Agents

Aromatic
aldehydes elicit their antisickling effects primarily
by increasing the affinity of hemoglobin (Hb) for oxygen (O2). However, challenges related to weak potency and poor pharmacokinetic
properties have hampered their development to treat sickle cell disease
(SCD). Herein, we report our efforts to enhance the pharmacological
profile of our previously reported compounds. These compounds showed
enhanced effects on Hb modification, Hb-O2 affinity, and
sickling inhibition, with sustained pharmacological effects in vitro. Importantly, some compounds exhibited unusually
high antisickling activity despite moderate effects on the Hb-O2 affinity, which we attribute to an O2-independent
antisickling activity, in addition to the O2-dependent
activity. Structural studies are consistent with our hypothesis, which revealed the compounds
interacting strongly with the polymer-stabilizing αF-helix could
potentially weaken the polymer. In vivo studies with
wild-type mice demonstrated significant pharmacologic effects. Our
structure-based efforts have identified promising leads to be developed
as novel therapeutic agents for SCD.