Convergent synthesis, kinetics and computational attributions of indole-N-phenyltriazole hybrids bearing N-(aryl)butanamides as alkaline phosphatase inhibitors

• Published in: Journal of Molecular Structure
• Main Author: Shakila; Abbasi M.A.; Aziz-ur-Rehman; Siddiqui S.Z.; Nazir M.; Raza H.; Shah S.A.A.; Ayine-Tora D.M.; Shahid M.; Kim S.J.
• Format: Article
• Language: English
• Published: Elsevier B.V. 2025
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85201787582&doi=10.1016%2fj.molstruc.2024.139649&partnerID=40&md5=226e3b1d8bc2d6570967dbc90f9e1377

In the research delineate herein, an innovative sequence of new series of multi-functional target molecules (9a-i) having indole-N-phenyltriazole bi-heterocyclic hybrids unified with N-arylated butanamides was synthesized as alkaline phosphatase inhibitor. The structural validation of all the formulated compounds was accomplished through IR, EI-MS, 1H NMR, 13C NMR and CHN analysis data. The in vitro enzyme inhibitory investigation revealed the efficacy of these bi-heterocyclic derivatives, 9a–i, as potent inhibitors of alkaline phosphatase relative to the standard used. The compound 9h was found to be the most active compound (IC50 = 0.062 ± 0.017 μM), and its inhibitory activity is about 10 times higher than potassium dihydrogen phosphate (KH2PO4) (IC50 = 5.251 ± 0.468 μM). The kinetics mechanism was attributed by evaluating the Lineweaver–Burk plots, which revealed that compound 9h inhibited the alkaline phosphatase non-competitively to form an enzyme–inhibitor complex. The inhibition constant Ki determined from Dixon plots for this compound was 0.045 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good interactions and binding energy values. These molecules also demonstrated mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, based on the presented results, these molecules, being the promising inhibitors of alkaline phosphatase, might be deliberated as suitable medicinal scaffolds to render normal calcification of bones and teeth. © 2024