Carbazole‐Linked 1,2,3‐Triazoles: In Vitro β‐Glucuronidase Inhibitory Potential, Kinetics, and Molecular Docking Studies

Abstract

β‐Glucuronidase enzyme is a tetrameric glycoprotein present in microsomes and lysosomes of many organs, and body fluids. Over‐expression of this enzyme is observed in several melanomas and carcinomas. Therefore, it has been identified as a target for the treatment of several pathological conditions. In this regard, carbazole linked 1,2,3‐triazoles (1–27) were synthesized according to our previous report, and evaluated for their in vitro β‐glucuronidase inhibitory activities. Compounds 7–10, 17–18, 20, and 22–27 showed potent activities with IC50 values between 0.55–32.5 μM, as compared to the standard, D‐saccharic acid 1,4‐lactone (IC50=45.75 ± 2.16 μM). All active compounds were found to be non‐cytotoxic against mouse fibroblast 3T3 cell line. Compounds 20, 22, 23, 25, 26, and 27 were subjected to enzyme kinetic studies for the determination of their modes of inhibition, and dissociation constants Ki. Compounds 23, 25, and 26 were also studied for their mode of inhibition by using molecular docking methods.

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

“…However, amide bond bioisostere, 1,2,3-triazole, is a stronger bGLU inhibitor compared to its 1,2,4-triazole isomer. Molecular hybridization with carbazole [203] delivered eight compounds having IC 50 < 3 mM (Fig. 32).…”

Synthesis of α‐Imino Amidines and 2,3‐Diamino Indolenines Using a One‐Pot Graphene Oxide‐Catalyzed Process

“…The operational simplicity, the limited number of steps, the heterogeneous catalytic nature of the process and the possibility to partial recover and reuse GO, bring our approach close to the concept of the ideal eco‐friendly synthesis [18] . The α ‐imino amidines 2 have never been reported in literature, though they can be considered useful synthetic intermediates, while the amino indolenines are privileged scaffolds, present in natural products, [19] bioactive compounds [20] and organic dyes [21] (Figure 1).…”

A New Carvotacetone Derivative from the Aerial Part of Sphaeranthus africanus

“…Several molecular models could retrieve the suggested protein-ligand complexes from the protein data bank (PDB) database, while software such as MOE Dock, AutoDock, and Surflex-Dock are good suggestions for the performance of docking. [14] In silico molecular docking is in the design of drug-delivery systems, [15,16] in α-glucosidase inhibition, [17][18][19] and to investigate antitumor agents, [20] FabH antibacterial inhibitors, [21] and Pim-1 Kinase inhibitors with a flexible-receptor docking protocol. [22] Recent investigation regarding docking in α-glucosidase inhibition which corresponded to the crystal structure of enzyme PDB ID: 4J5T.…”