Experimental and computational investigation of the α-amylase catalyzed Friedel-Crafts reaction of isatin to access symmetrical and unsymmetrical 3,3′,3′′-trisindoles

Trisindoles are of tremendous interest due to their wide range of biological activities. In this context, a number of methods have been reported in the past to synthesize 3,3 ',3 ''-trisindoles. However, most of the methods are only able to produce symmetrical 3,3 ',3 ''-trisindoles. Herein, we develop a sustainable and efficient approach to synthesize symmetrical as well as unsymmetrical 3,3 ',3 ''-trisindoles in a very selective manner using the alpha-amylase enzyme as a catalyst. Furthermore, various differently substituted isatin and indoles were used to prove the generality of the protocol and symmetrical or unsymmetrical 3,3 ',3 ''-trisindoles were obtained in 43-97% isolated yields. Next, a probable mechanism is proposed and investigated using molecular dynamics (MD) investigation to gain more insight into the role of residues available in the active site of the alpha-amylase enzyme. These studies revealed that Glu230, Lys209, and Asp206 in the active site of alpha-amylase play an important role in this catalysis. Moreover, the DFT studies suggested the formation of bisindole and alkylideneindolenine intermediates during the transformation. We synthesized four different biologically important 3,3 ',3 ''-trisindoles on a gram scale, which proved the robustness and scalability of this protocol. A highly selective and sustainable approach using alpha-amylase enzyme to synthesize biologically important symmetrical as well as unsymmetrical 3,3 ',3 ''-trisindoles has been reported.