Convergent Synthesis, Kinetics and Computational Comprehensions of Indole- (Phenyl)triazole Bi-heterocycles Amalgamated with Propanamides as Elastase Inhibitors

Abstract In the study presented here, 4-(1H-indol-3-yl)butanoic acid was sequentially converted into ethyl 4-(1H-indol-3-yl)butanoate, 4-(1H-indol-3-yl)butanohydrazide and 5-[3-(1H-indol-3-yl)propyl]-1,2,4-triazole-2-thiol as a nucleophile. In a parallel series of reactions, various electrophiles were synthesized by reacting aryl amines with 3-bromopropanoyl chloride to afford N-(aryl)-3-bromopropanamides. Then the nucleophilic substitution reaction of 5 was carried out with different electrophiles, to achieve final bi-heterocyclic derivative. The structural confirmation of all the synthesized compounds was done by IR, 1H-NMR, 13C-NMR and CHN analysis data. The inhibitory effects of these bi-heterocyclic propanamides were evaluated against elastase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 9d inhibited elastase competitively to form an enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 0.51 µM. These molecules also exhibited mild cytotoxicity toward red blood cell membranes, when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds for dealing with the elastase related ailments such as lungs diseases, cyclic neutropenia, pruritic skin disease and liver infection.