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 α-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 α-amylase enzyme. These studies revealed that Glu230, Lys209, and Asp206 in the active site of α-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.

Enzymatic Synthesis of Indole-Based Imidazopyridine using α-Amylase.

The imidazo[1,2-a]pyridine scaffold has gained significant attention due to its presence as a lead structure in several commercially available pharmaceuticals like zolimidine, zolpidem, olprinone, soraprazan, etc. Further, indole-based imidazo[1,2-a]pyridine derivatives have been found interesting due to their anticancer and antibacterial activities. However, limited methods have been reported for the synthesis of indole-based imidazo[1,2-a]pyridines. In this study, we have successfully developed a biocatalytic process for synthesizing indole-based imidazo[1,2-a]pyridine derivatives using the α-amylase enzyme catalyzed Groebke-Blackburn-Bienayme (GBB) multicomponent reaction of 2-aminopyridine, indole-3-carboxaldehyde, and isocyanide. The generality and robustness of this protocol were shown by synthesizing differently substituted indole-based imidazo[1,2-a]pyridines in good isolated yields. Furthermore, to make α-amylase a reusable catalyst for GBB multicomponent reaction, it was immobilized onto magnetic metal-organic framework (MOF) materials [Fe3 O4 @MIL-100(Fe)] and found reusable up to four consecutive catalytic cycles without the significant loss in catalytic activity.