Convergent Synthesis, Kinetics, and Computational Studies of Indole(Phenyl)Triazole Bi-Heterocycles Modified With Propanamides as Elastase Inhibitors

• Published in: Chemistry and Biodiversity
• Main Author: Shakila; Abbasi M.A.; Aziz-ur-Rehman; Siddiqui S.Z.; Nazir M.; Muhammad S.; Raza H.; Shah S.A.A.; Shahid M.; Chaudhry A.R.; Kim S.J.
• Format: Article
• Language: English
• Published: John Wiley and Sons Inc 2024
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85211091023&doi=10.1002%2fcbdv.202401806&partnerID=40&md5=39c820e1eb9b3df5a352f68a66cec7b3

Biological screening combined with the synthesis of heterocyclic compounds with numerous functions is the most effective approach available for pharmacological assessment of potential future medications. In the under taken research that is presented here, 4-(1H-indol-3-yl)butanoic acid was sequentially converted into 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. By treating aryl amines with 3-bromopropanoyl chloride in a series of parallel reactions, different electrophiles were created, leading to the formation of N-(aryl)-3-bromopropanamides. After that, several electrophiles were used in the nucleophilic substitution process of 5 to produce the 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 enzyme inhibitory effects of these bi-heterocyclic propanamides were evaluated against elastase, and all these molecules were identified as potent inhibitors relative to the standard oleanolic acid with IC50 value 13.453 ± 0.015 µM 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. Compound 9d’s activity (IC50 = 0.142 ± 0.014 µM) significantly increased when a slightly bulky ethyl group was replaced for the solitary methyl group in 9c at the para-position. However, compound 9e’s activity was significantly lower (IC50 = 38.338 ± 0.993 µM) when a more polar ethoxy group was replaced at the same para-position. This was likely because of electronic considerations. These molecules also exhibited mild cytotoxicity toward red blood cell membranes, when analyzing through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds for dealing with the elastase-related ailments such as lung diseases, cyclic neutropenia, pruritic skin disease, and liver infection. © 2024 Wiley-VHCA AG, Zurich, Switzerland.