Multi-step synthesis, kinetics and in silico explorations of indole-Phenyl-1,2,4-triazole Bi-heterocyclic hybrids unified with 3-substituted benzamides as elastase inhibitors

• Published in: Journal of molecular structure 2025-02, Vol.1322, p.140192, Article 140192
• Main Authors: Shakila, Abbasi, Muhammad Athar, Aziz-ur-Rehman, Siddiqui, Sabahat Zahra, Nazir, Majid, Muhammad, Shabbir, Raza, Hussain, Shah, Syed Adnan Ali, Shahid, Muhammad, Chaudhry, Aijaz Rasool, Kim, Song Ja
• Format: Article
• Language: English
• Subjects: Benzamides; Elastase; Hemolysis; Kinetic mechanism; Molecular docking
• ISSN: 0022-2860
• DOI: 10.1016/j.molstruc.2024.140192

•Designing of Indole-Phenyl-1,2,4-Triazole Bi-Heterocyclic.•Determining of In-vitro elastase inhibitory potential and kinetics.•Establishing the structure-activity relationships.•In-silico computational studies to supplement the In-vitro results.•Exploration of these molecules against elastase for elastase-related ailments. In the present research work, a library of unique indole-phenyltriazole hybrids comprising 3-substituted-benzamide moiety was synthesized through convergent multi-step strategy. The structural confirmation of all synthesized molecules was corroborated by IR, 1H NMR, 13C MMR, EI-MS and CHN analysis data. The results of in vitro inhibitory potential of novel benzamides against elastase enzyme revealed that all molecules were potent inhibitors and 10d was most active compound among them having IC50 value of (0.197 ± 0.027 µM), relative to the standard (13.421 ± 0.016 µM). The Kinetics mechanism analyzed by Lineweaver-Burk plots which exposed that 10d inhibited this enzyme competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki determined from Dixon plot for compound 10d was 0.85 µM. Moreover, cytotoxicity of these compounds was also profiled by hemolytic activity and it was observed that almost all these benzamides compounds displayed low cytotoxicity. These molecules also exhibited mild cytotoxicity toward red blood cell membrane. In addition, the in silico computational explorations fully supported the in vitro enzyme inhibitory results. The binding energy ranges from -7.1 to -9.1 kcal/mol, which showed that compound possessed good interaction tendencies to the pancreatic elastase target protein. So, it was anticipated from the experimental results and computational investigations of the current research that these derivatives might lead to further research gateways for obtaining better and safe nontoxic medicinal scaffolds for dealing with the elastase related ailments such as lungs diseases, pruritic skin disease and liver infection. [Display omitted]