Rhodanine-benzamides as potential hits for -amylase enzyme inhibitors and radical (DPPH and ABTS) scavengers

A series of 3-substituted and 3,5-disubstituted rhodanine-based derivatives were synthesized from 3-aminorhodanine and examined for alpha-amylase inhibitory, DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities in vitro. These derivatives displayed significant alpha-amylase inhibitory potential with IC50 values of 11.01-56.04 mu M in comparison to standard acarbose (IC50 = 9.08 +/- 0.07 mu M). Especially, compounds 7 (IC50 = 11.01 +/- 0.07 mu M) and 8 (IC50 = 12.01 +/- 0.07 mu M) showed highest alpha-amylase inhibitory activities among the whole series. In addition to alpha-amylase inhibitory activity, all compounds also demonstrated significant scavenging activities against DPPH and ABTS radicals, with IC50 values ranging from 12.24 to 57.33 and 13.29-59.09 mu M, respectively, as compared to the standard ascorbic acid (IC50 = 15.08 +/- 0.03 mu M for DPPH; IC50 = 16.09 +/- 0.17 mu M for ABTS). These findings reveal that the nature and position of the substituents on the phenyl ring(s) are crucial for variation in the activities. The structure-activity relationship (SAR) revealed that the compounds bearing an electron-withdrawing group (EWG) at para substitution possessed the highest activity. In kinetic studies, only the km value was changed, with no observed changes in Vmax, indicating a competitive inhibition. Molecular docking studies revealed important interactions between compounds and the alpha-amylase active pocket. Further advanced research needs to perform on the identified compounds in order to obtain potential antidiabetic agents.