Synthesis of indole based acetohydrazide analogs: Their in vitro and in silico thymidine phosphorylase studies

• Published in: Bioorganic chemistry 2020-05, Vol.98, p.103745, Article 103745
• Main Authors: Taha, Muhammad, Aldhamin, Ebaa Ahmed Jassim, Almandil, Noor Barak, Anouar, El Hassane, Uddin, Nizam, Alomari, Munther, Rahim, Fazal, Adalat, Bushra, Ibrahim, Mohamad, Nawaz, Fasial, Iqbal, Naveed, Alghanem, Bandar, Altolayyan, Abdulelah, Khan, Khalid Mohammed
• Format: Article
• Language: English
• Subjects: Acetohydrazide; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli - enzymology; Hydrazines - chemical synthesis; Hydrazines - chemistry; Hydrazines - pharmacology; Indoles - chemistry; Indoles - pharmacology; Molecular docking; Molecular Docking Simulation; Molecular Structure; Recombinant Proteins - metabolism; SAR; Structure-Activity Relationship; Synthesis; Thymidine phosphorylase; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine Phosphorylase - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103745

[Display omitted] •Synthesis of indole analogues.•In vitro thymidine phosphorylase studies.•Identification of a new thymidine phosphorylase.•Structure Activity Relationship established.•Molecular docking. In this study, a series of indole based acetohydrazide derivatives (1–22) were synthesized and characterized by 13C NMR, 1H NMR and HREI-MS. The resulted derivatives were tested for thymidine phosphorylase inhibitory potential. These derivatives inhibited thymidine phosphorylase at different concentration ranging from 1.10 ± 0.10 to 41.10 ± 1.10 µM when compared with the standard 7-Deazaxanthine (IC50 value 38.68 ± 1.12 µM). The compound 8 having OH group at 2, 4 and 6 position was found the most potent among the series with IC50 1.10 ± 0.10 µM. The structure activity relationships (SAR) has been established for all compounds keeping in the view the role of substitution and the effect of functional group which significantly affect thymidine phosphorylase activity. The nature of binding interactions of the most potent compounds and active sites of the enzymes was confirmed through molecular docking study.