New neuroprotective derivatives of cinnamic acid by biotransformation

Abstract

Microbial transformation is extensively utilized to generate new metabolites in bulk amounts with more specificity and improved activity. As cinnamic acid was reported to exhibit several important pharmacological properties, microbial transformation was used to obtain its new derivatives with enhanced biological activities. By manipulating the 2-stage fermentation protocol of biotransformation, five metabolites were produced from cinnamic acid. Two of them were new derivatives; <i>N</i>-propyl cinnamamide 2̲ and 2-methyl heptyl benzoate 3̲ produced by <i>Alternaria alternata</i>. The other 3 metabolites, <i>p</i>-hydroxy benzoic acid 4̲, cinnamyl alcohol 5̲ and methyl cinnamate 6̲, were produced by <i>Rhodotorula rubra</i>, <i>Rhizopus</i> species and <i>Penicillium chrysogeneum</i>, respectively. Cinnamic acid and its metabolites were evaluated for their cyclooxygenase (COX) and acetylcholinesterase (AChE) inhibitory activities. Protection against H₂O₂ and Aβ_1-42 induced-neurotoxicity in human neuroblastoma (SH-SY5Y) cells was also monitored. Metabolite 4̲ was more potent as a COX-2 inhibitor than the parent compound with an IC₅₀ value of 1.85 ± 0.07 μM. Out of the tested compounds, only metabolite 2̲ showed AChE inhibitory activity with an IC₅₀ value of 8.27 μM. These results were further correlated with an <i>in silico</i> study of the binding interactions of the active metabolites with the active sites of the studied enzymes. Metabolite 3̲ was more potent as a neuroprotective agent against H₂O₂ and Aβ_1-42 induced-neurotoxicity than catechin and epigallocatechin-3-gallate as positive controls. This study suggested the two new metabolites 2̲ and 3̲ along with metabolite 4̲ as potential leads for neurodegenerative diseases associated with cholinergic deficiency, neurotoxicity or neuroinflammation.