Santos_2020_Bioorg.Med.Chem__115470

Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer's disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 muM) at 96.1 +/- 5.5%, 90 +/- 2.1%, 100.3 +/- 1.7%, 80.1 +/- 9.4% and 82.2 +/- 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 +/- 1.7% of AChE activity (100 muM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe(2+) and Zn(2+) ions in a 2:1 ligand:metal ratio according to the Job Plot method.