Cinnamic acid conjugated with triazole acetamides as anti-Alzheimer and anti-melanogenesis candidates: an in vitro and in silico study
Amir Shervin Shokouhi Asl, Mohammad Hosein Sayahi, Mohammad Hashem Hashempur, Cambyz Irajie, AmirHossein Alaeddini, Seyedeh Niloufar Ghafouri, Milad Noori, Navid Dastyafteh, Javad Mottaghipisheh, Mehdi Asadi, Bagher Larijani, Mohammad Mahdavi, Aida Iraji
Abstract
In this study, new cinnamic acid linked to triazole acetamide derivatives was synthesized and evaluated for anti-Alzheimer and anti-melanogenesis activities. The structural elucidation of all analogs was performed using different analytical techniques, including 1 H-NMR, 13 C-NMR, mass spectrometry, and IR spectroscopy. The synthesized compounds were assessed in vitro for their inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase enzymes. Among synthesize derivative compound 3-(4-((1-(2-((2,4-dichlorophenyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)acrylic acid ( 10j) exhibited the highest activity against BChE with an IC 50 value of 11.99 ± 0.53 µM. Derivative 3-(3-methoxy-4-((1-(2-oxo-2-(p-tolylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acrylic acid ( 10d) , bearing a 4-CH 3 group, was identified as the most potent AChE inhibitor. In terms of tyrosinase inhibition, 3-(3-methoxy-4-((1-(2-((2-methyl-4-nitrophenyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acrylic acid (compound 10n) , demonstrated 44.87% inhibition at a concentration of 40 µM. Additionally, a kinetic study of compound 10j which 2,4-dichlorophenyl substituents against BChE revealed a mixed-type inhibition pattern. Furthermore, molecular docking and molecular dynamic studies of compound 10j were conducted to thoroughly evaluate its mode of action within the BChE active site.