Isomerization of bioactive acylhydrazones triggered by light or thiols

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biochemistry

Background:

• Acylhydrazone scaffolds are prevalent in screening libraries for identifying ligands against biological targets.
• Numerous bioactive acylhydrazones have been documented, but their potential for E/Z isomerization around the C=N bond is often overlooked during bioactivity assays.

Purpose of the Study:

• To investigate the impact of E/Z isomerization on the bioactivity of ortho-hydroxylated acylhydrazones.
• To explore the role of cellular components, such as glutathione, in mediating acylhydrazone isomerization.

Main Methods:

• Analysis of ortho-hydroxylated acylhydrazones identified via virtual screening for N-methyl-D-aspartate receptor modulators.
• Examination of other bioactive hydroxylated acylhydrazones with known structures from the Protein Data Bank.
• Investigation of photoisomerization of ionized acylhydrazone forms under laboratory conditions.
• Assessment of glutathione-catalyzed E⇄Z isomerization dynamics.

Main Results:

• Ionized forms of ortho-hydroxylated acylhydrazones readily photoisomerize under laboratory conditions.
• The E and Z isomers exhibit significantly different bioactivities.
• Glutathione catalyzes dynamic E⇄Z isomerization of acylhydrazones.
• The ratio of E to Z isomers within cells is dictated by the relative thermodynamic stabilities of the isomers.

Conclusions:

• E/Z isomerization is a critical, often unexamined, factor influencing the observed bioactivity of acylhydrazone compounds.
• The study highlights the need for routine analysis of E/Z isomerization in the development and assessment of acylhydrazone-based therapeutics.