Pyridyl Derivatives of Benzaldehyde as Potential Antisickling Agents

Abstract

Compounds that bind to sickle hemoglobin (Hb S) producing an allosteric shift to the high-affinity Hb S that does not polymerize are being developed to treat sickle cell anemia (SCA). In this study, three series of pyridyl derivatives of substituted benzaldehydes (Classes I-III) that combine structural features of two previously determined potent antisickling agents, vanillin and pyridoxal, were synthesized. When analyzed with normal human whole blood, the compounds form Schiff-base adducts with Hb and left shift the oxygen equilibrium curve (OEC) to the more soluble high-affinity Hb, more than vanillin or pyridoxal. Generally, Class-I compounds with an aromatic aldehyde located ortho to the pyridyl substituent are the most potent, followed by the Class-II compounds with the aldehyde at the meta-position. Class-III compounds with the aldehyde at the para position show the weakest activity. The structure-activity studies of these pyridyl derivatives of substituted benzaldehydes demonstrate significant allosteric potency that may be useful for treating SCA.

Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

“…41,46 These compounds (INN) bind to the same Hb site as 5-HMF and exhibit superior left-shifting ability and antisickling activities, some exhibiting as much as 90-fold and 2.5-fold potency than vanillin and 5-HMF, respectively. 41,46 Similar to 5-HMF, the INN compounds also bind to the α-cleft to form Schiff-base adducts with the N-terminal αVal1 nitrogen (Fig. 5), and through a series of direct and intricate water-mediated interactions (via the hydroxyl moiety) tie the two α-subunits together to stabilize the relaxed state in the R2 form.…”

100 years of sickle cell disease research: etiology, pathophysiology and rational drug design (part 1)

“…This observation was confirmed by the crystallographic results implied the importance of the hydroxyl moiety of 5-HMF in the stabilization of the relaxed R state of hemoglobin [61]. Based on these results and using vanillin and pyridoxal (previously studied antisickling non-toxic aldehyde) [37] as scaffold, several pyridyl derivatives (INN) were developed and evaluated for their antisickling activity [1,50,62]. Amazingly, some of these compounds showed as much as 90 and 2.5-foldpotency compared to vanillin and 5-HMF, respectively, although they bind at the same site of hemoglobin as 5-HMF [1].…”

“…In the same study, it was stated that the allosteric activity of these pyridyl derivatives is highly related to the position of the methoxy and pyridyl groups with respect to the aldehyde function. Generally, ortho-pyridyl benzaldehyde derivatives having a meta or para-methoxy substitution showed the highest activity, as in compound INN312, which act as a stereospecific inhibitor of the deoxy-HbS polymer while efficiently increasing the Hb affinity for oxygen [50].…”

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

“…Targeting sickle hemoglobin for inhibitor design does not only aim to directly inhibit its aggregation into multi-stranded polymers, but also includes approaches that either result in the stabilization of the R conformation of the HbS molecule, or the destabilization of the T conformer [105,106]. Compounds whose antisickling properties are based on this concept include vanillin and pyridyl derivatives of vanillin, 5-hydroxymethylfurfural (5-HMF), and the recently approved voxelotor (GBT 440) [54,99,[106][107][108][109][110]. They bind to the N-terminal valine (and possibly lysine) residues of the α-globin chains of HbS ( Figure 4) [98], forming a reversible Schiff-base adduct which stabilizes the R-state and/or destabilizes the T-state, increasing hemoglobin solubility, and thus inhibiting HbS aggregation.…”