New neuroprotective derivatives of cinnamic acid by biotransformation

Hadeer Elkharsawy; Ramadan A. Eldomany; Amira Mira; Amal F. Soliman; Mohamed Amir; Saleh El-sharkawy

doi:10.1039/D3FO04802K

New neuroprotective derivatives of cinnamic acid by biotransformation†

Hadeer Elkharsawy,^a Ramadan A. Eldomany,^b Amira Mira,

*^cd Amal F. Soliman,^de Mohamed Amir^f and Saleh El-sharkawy^d

Author affiliations

* Corresponding authors

^a Department of Pharmacognosy, Faculty of Pharmacy, Kafr El-Sheikh University, Kafr El-Sheikh 33516, Egypt

^b Department of Microbiology and Immunology, Faculty of Pharmacy, Kafr El-Sheikh University, Kafr El-Sheikh 33156, Egypt

^c Department of Pharmacognosy & Pharmaceutical Chemistry, College of Dentistry & Pharmacy. Buraydah Private Colleges, Buraydah 51418, Kingdom of Saudi Arabia
E-mail: Amira.Mera@bpc.edu.sa, amira_mera2006@mans.edu.eg
Tel: +966 535800915

^d Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt

^e Pharmacognosy Department, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt

^f Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt

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; N-propyl cinnamamide and 2-methyl heptyl benzoate produced by Alternaria alternata. The other 3 metabolites, p-hydroxy benzoic acid , cinnamyl alcohol and methyl cinnamate , were produced by Rhodotorula rubra, Rhizopus species and Penicillium chrysogeneum, 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 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 showed AChE inhibitory activity with an IC₅₀ value of 8.27 μM. These results were further correlated with an in silico study of the binding interactions of the active metabolites with the active sites of the studied enzymes. Metabolite 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 and along with metabolite as potential leads for neurodegenerative diseases associated with cholinergic deficiency, neurotoxicity or neuroinflammation.