Rational Design, Synthesis and Biological Characterization of Novel Antisickling Agents with Enhanced Metabolic Stability

Author

• Albert Opare, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/n9ns-fh20

Author ORCID Identifier

https://orcid.org/0009-0000-5442-101X

Defense Date

2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmaceutical Sciences

First Advisor

Yan Zhang

Abstract

Sickle cell disease (SCD) is caused by a mutation (Glu6Val6) in the β-globin chain of adult hemoglobin (HbA), resulting in sickle hemoglobin (HbS). When deoxygenated, HbS molecules polymerize, causing red blood cell (RBC) sickling, vaso-occlusion, painful crises and organ damage. Although several FDA-approved treatments are available, issues like toxicity, low efficacy and high cost limit their use, highlighting the need for more efficacious, non-toxic, and affordable therapy for SCD. Aromatic aldehydes offer an alternative approach to treatment. They bind to Hb, forming Schiff-base with the α-subunit to increase the non-polymer forming high-O₂ affinity Hb and/or directly disrupt the polymer. Our group has developed several aromatic aldehydes including PP compounds. Although potent, the PP compounds are metabolized at the ester to the acid-form metabolite in vivo, which could potentially lead to adverse effect.

We therefore designed 64 amide analogs of the lead compounds - PP10 and PP14, which we hypothesized would be more metabolically stable whilst preserving antisickling property. Out of 48 compounds tested, 17 inhibited RBC sickling >50% under anoxic conditions, comparable to VZHE061 (ILX-002), one of our lead compounds. Structure-activity relationship studies showed that mono-substituted amides were generally more potent. Expectedly, VZHE098, demonstrated improved metabolic stability in vitro compared with PP14. In vivo however, VZHE098 and its benzene analog VZHE085, were hydrolyzed. That notwithstanding, the improved stability of VZHE098 in vitro, warrants in vivo PK/PD exploration of other amide analogs. A second-generation analog, VZHE160, was also developed by introducing a hydroxyl group to enhance stability and Hb interactions.

Rights

© Albert Opare

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-7-2026