Synthesis of indole analogs as potent β-glucuronidase inhibitors

• Published in: Bioorganic chemistry 2017-06, Vol.72, p.323-332
• Main Authors: Baharudin, Mohd Syukri, Taha, Muhammad, Imran, Syahrul, Ismail, Nor Hadiani, Rahim, Fazal, Javid, Muhammad Tariq, Khan, Khalid Mohammed, Ali, Muhammad
• Format: Article
• Language: English
• Subjects: Docking; Dose-Response Relationship, Drug; Glucuronidase - antagonists & inhibitors; Glucuronidase - metabolism; Glycoproteins - chemical synthesis; Glycoproteins - chemistry; Glycoproteins - pharmacology; Humans; Indole; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Molecular Structure; Structure-Activity Relationship; Synthesis; β-glucuronidase inhibition
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2017.05.005

[Display omitted] •Synthesis of indole derivatives.•In vitro β-glucuronidase inhibitory activity.•Identification of a novel class of β-glucuronidase inhibitors.•Molecular docking. Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against β-glucuronidase inhibitory is utmost essential. In this study indole analogs (1–35) were synthesized, characterized using various spectroscopic techniques including 1H NMR and EI-MS and evaluated for their β-glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC50 values ranging between 0.50 and 53.40μM, with reference to standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oε1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with acid-base catalyst Glu451 (3.96Å) and thus preventing Glu451 from functioning as proton donor residue.