#186 Design, synthesis and evaluation of dual MAO/AChE inhibitory capabilities of some novel substituted aryl hydrazones

Abstract

Monoamine oxidase A and B (MAO-A/B) are FAD-containing enzymes found in the outer mitochondrial membrane and are responsible for the oxidative deamination of biogenic monoamines. The tissue distribution of MAO-B is more (80%) in the brain. The high concentration of MAO-B in the brain decreases dopamine level and increase oxidative stress. On the other hand, acetylcholinesterase (AChE) catalyzes the hydrolysis of acetylcholine (ACh) into acetate ions and choline in neuronal synapses. The high activity of AChE causes depletion of acetylcholine levels in the brain and periphery, which leads to impaired learning and memory deficit. Recently we have identified a piperonylic acid-derived hydrazone (Fig. 1) as a potent dual MAO/AChE inhibitor. In order to investigate the role of benzodioxole moiety in the lead inhibitor (SBH-3) on the enzyme activity, we designed a series of open chain (01-07) and simple (08-16) aryl hydrazones using the ligand-guided design and optimization strategy. The synthesis of designed molecules was accomplished by multistep synthesis starting from dimethoxy benzoic acid (compounds 01-07) and 4-chlorophenylacetic acid (compounds 08-16). All synthesized hydrazones were characterized by using IR, NMR, and Mass spectral techniques, and their dual enzyme inhibitory potential was evaluated against MAO-B and AChE using colorimetry assay and Ellman’s method, respectively. A set of 16 compounds was designed, synthesized, and evaluated against MAO-B and AChE. The tested compounds showed nanomolar to micromolar inhibitory potential with IC$_{50}$ values between 7.009±0.012 µM (Compound 03) between 16.998±0.023 µM (Compound 04) against MAO-B, whereas for AChE, the IC$_{50}$ values ranged from 0.024±0.007 µM (Compound 03) to 69.096±0.54 µM (Compound 11). The open-chain analog, compound 03, emerged as a lead AChE inhibitor with an IC$_{50}$ value of 0.052±0.006 µM. Thus, the lead optimization study yielded a selective AChE inhibitor (compound 03) that is two times more potent than the earlier dual inhibitor SBH-3. Based on the results, it can be concluded that the presence of a bulky hydrophobic benzodioxole moiety at the amido terminal highly influences the selective and dual AChE/MAO-B inhibition potential of aryl hydrazones.

Fig. Ligand-based design strategy and the structure of the lead compound