Ultrasonic-assisted synthesis of amantadine derivatives-in vitro urease and α-glucosidase inhibitory activities, mechanistic, and computational studies

Abstract

Ultrasonic synthesis of 26 amantadine derivatives, (3-28) including seven new compounds, are reported with significantly reduced synthesis time and increased percentage yield relative to literature data. Evaluation of the urease, and α-glucosidase enzyme inhibitory activities of all amantadine derivatives are being reported here for the first time. Three compounds were found to be potent urease inhibitors (IC50 = 9.32 ± 1.01 µM, to IC50 = 11.32 ± 1.05 µM) as compared to the standard drug acetohydroxamic acid (IC50 = 20.3 ± 0.4 µM). Five compounds were found to be potent inhibitors of α-glucosidase (IC50 = 40.63 ± 1.70, to 50.07 ± 1.73) as compared to standard drug acarbose (IC50 = 875.75 ± 2.08 µM). Kinetic studies were performed to investigate competitive and non-competitive inhibition of α-glucosidase enzymes and mixed type inhibition of urease enzyme. All compounds along with parent drug was checked for their cytotoxicity against human fibroblast (B.J.) cell line. Four compounds were found to be toxic, while the rest were nontoxic.Furthermore, in silico studies were performed to predict the binding interactions of the compounds at the active site of the enzymes. The two most active adamantane analogs against urease are those with m- and o-fluoro substitution due to specific interactions with CME592, HOH1918 and GLN635 (3.04, 2.74, and 3.21 Å). Ortho analogs interact with GLN635 (3.04, 3.10 Å). The two analogs having diflouro and tri flouro methyl group, showed a slight lower activity as compared to the first two compounds. This analysis clearly indicates the importance of position of fluoro group in urease inhibition activity. Similarly, in α-glucosidase inhibitors, three compounds with p-OCH3, ethyl groups, and di-fluoro were found to be the most active inhibitors in excellent agreement with experimental data. This study identifies new analogs with potent α-glucosidase and urease inhibitory activities. and, thus, may be of therapeutic importance.