Indium-Catalyzed Direct Amidation Reaction of Carboxylic Acids and In Silico Study for Screening the Activity of Potential Therapeutics of the Synthesized Products

Amide bonds are ubiquitous and valuable motifs in synthetic chemistry, found in a wide range of applications such as the backbone of proteins and pharmaceutical agents. Thus, environmentally friendly and selective methods for synthesizing amide bonds are important. Herein, we report a simple, efficient, and rapid route to access a range of functionalized amides from non-activated carboxylic acids and amines using indium (III) trifluoromethanesulfonate as an efficient catalyst. A wide range of carboxylic acids - including aliphatic, aromatic, heterocyclic, and dicarbonyl acids - participate smoothly in these reactions, generating structurally diverse amides in moderate to good yields (up to 91 % in 24 examples). The reactions are conducted in dry tetrahydrofuran (THF) under reflux conditions. Furthermore, this amidation strategy provides a method for addressing challenging molecules, such as protected amino acids, to produce biocompatible products. These products can then be used as substrates for various organic transformations, including C-H functionalization reactions. We also demonstrate the synthetic utility of our protocol through the synthesis of essential substrates in organic and medicinal chemistry by reacting N-protected carboxylic acids with 8-aminoquinoline to produce a series of biologically valuable compounds. Five of these products, named 4 f, 4p, 9a, 9c, and 9d, have been biologically evaluated through an in-silico study. The interaction of these compounds with receptor protein 8DQT was examined to assess their potential as drug candidates for hypertension treatment. Effective binding was detected between these compounds and the receptor. Data from molecular docking studies show that compounds 4d and 4 m are the most active, with binding scores of -8.8 and -8.6 kcal/mol, respectively. However, compound 4 m exhibited a stronger binding affinity than compound 4d over the course of dynamic simulation. Our ADMET study suggests that all five compounds are highly safe in the body. Based on the BOILED-Egg model study, good absorption is suggested for all the molecules, and they can cross the blood-brain barrier. A rapid, efficient, and eco-friendly method is developed to produce a range of functionalized amides from non-activated carboxylic acids and amines with indium (III) trifluoromethanesulfonate as a catalyst. Five synthesized compounds are evaluated and approved as potential hypertension drugs through molecular docking and dynamic simulation studies with 3-phosphoinositide-dependent protein kinase-1 (PDK1). image