InCl3-catalyzed three-component Aza-Friedel-Crafts reactions of Aldehydes, 4-Aminofluorescein, and indoles in methanol have been developed. The Aza-Friedel-Crafts products could be easily transformed into various 3-substituted indoles including biologically active compounds. This system offers a novel efficient method for the synthesis of 3-substituted indole derivatives in good yields. Further, the molecules are predicted to bind with Induced myeloid leukemia cell differentiation protein Mcl-1 using Extended Connectivity fingerprint ECfp4 NN (ECfp4)+NB (ECfp4). Molecular docking studies with Mcl-1 showed a docking score of -7.8 kcal/mol with two hydrogen bonds and nine hydrophobic contacts by interaction with the R263 hot-spots implying a potential inhibitor against Mcl-1.The Aza-Friedel-Crafts reactions (AFCR) have attracted much attention as a synthetically outstanding carbon-carbon bond-forming process that leads to functionalized amines in a green transformation and completely atom-economicF way. However, in spite of its significance, many potential problems related to arene nucleophile, electrophilic substrate, or functional group tolerance still remain for this transformation. For example, the Aza-Friedel-Crafts reaction seems to be restricted to highly electrophilic substrates, such as trifluoromethyl imines, and highly nucleophilic substrates, such as indoles, electron-rich arenas due to the low reactivity of imines. In addition, the one-pot Multicomponent Coupling Reactions (MCRs), which introduce several elements of diversity into a molecule in a single step. For a long time, the transition metal-catalyzed Multi-Component Reactions (MCRs) have attracted much interest because of their capability of offering many challenging transformations using one-pot method. Particularly those metal catalysts, which are derived from the group VIII-X metals, display remarkable efficiency for the formation of carbon-carbon and carbon-heteroatom bonds. Furthermore, Piersanti and co-workers reported the reaction using enamines derived from α-ketoesters with indoles to give products with moderate enantioselectivities. The recently reported the highly enantioselective Aza-Friedel-Crafts reaction of 2-substituted-3H-indol-3-one derivatives with pyrroles using novel chiral imidazoline-phosphoric acid catalysts.

Prediction of ligands based target protein was performed using Extended Connectivity fingerprint ECfp4 NN (ECfp4)+NB (ECfp4) of the PPB2 server. Extended-Connectivity Fingerprints (ECFPs) are circular topological fingerprints designed for molecular characterization, similarity searching, and structure-activity modeling. It is among the most popular similarity search tools in drug discovery and they are effectively used in a wide variety of applications. NB (ECfp4) stands for a multinomial Naive Bayes model built on a reference database (~350K compounds and 1720 targets) extracted from ChEMBL using ECfp4 fingerprint. This model was built only once and uses to predict the targets for any query molecule. NN (ECfp4) is a similarity searching based target predictions method using ECfp4 fingerprint. Initially the similarity between a query molecule and each of the compounds in the reference database and followed by sorting of the compounds in the reference database as per similarity score. The top 2000 compounds (nearest neighbor of a query) selected from the reference database and collect the targets associated with these top 2000 compounds. Scoring is performed as per the similarity of the most similar nearest neighbor associated with a target.The best target predicted from the PPB2 server was used to further studies. The protein structure of Estrogen receptor alpha, Mcl-1, and Progesterone receptor was modeled using the Swiss model server. The 3D structure of the protein and the small molecules were obtained and converted to the PDBQT file. The active site amino acids were determined using PDBSum  from the PDB ids: 3ERT, 4WMR, and 2OVH respectively. Docking was performed using the grid for the whole protein with a default value of 0.375 Å with exhaustiveness of 24 using AutodockVina . The interaction of the molecule and the protein was further analyzed using Discovery studio.In conclusion, we have demonstrated a very simple, efficient, and practical method for the one-pot Aza-Friedel-Crafts reactions of 3-substituted indole derivatives from Aldehyde, Indole, and aromatic amines in the presence of a catalytic amount of Indium trichloride. The existence of the methine hydrogen (sp3 C-H) was identified from 1H and 13C NMR studies. Preliminary In-silico studies on this molecule have shown that it interacts with Mcl-1 efficiently at the Arg 263 position, which is a hotspot of Mcl-1. The major advantage of this method is that it is truly a one-pot procedure that does not require a separate step to prepare an imine for subsequent use. The significant features of the protocol include operational simplicity, inexpensive reagents, mild condition, and high yields of the products. Further in vivo and in vitro studies on the molecule will help in understanding the efficiency of the molecule as an anticancer agent.

Warm Regards,
Alisha
Journal Coordinator
Journal of Translational Neurosciences