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

Muhammad Taha; Ebaa Ahmed Jassim Aldhamin; Noor Barak Almandil; El Hassane Anouar; Nizam Uddin; Munther Alomari; Fazal Rahim; Bushra Adalat; Mohamad Ibrahim; Fasial Nawaz; Naveed Iqbal; Bandar Alghanem; Abdulelah Altolayyan; Khalid Mohammed Khan

doi:10.1016/j.bioorg.2020.103745

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

Bioorg Chem. 2020 May:98:103745. doi: 10.1016/j.bioorg.2020.103745. Epub 2020 Mar 12.

Authors

Affiliations

¹ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia. Electronic address: mtaha@iau.edu.sa.
² College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
³ Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
⁴ Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University, P.O. Box 83, Al Kharj 11942, Saudi Arabia.
⁵ Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
⁶ Department of Stem Cell Biology, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia.
⁷ Department of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan.
⁸ Department of Chemistry, University of Wah, Quaid Avenue, Wah Cantt 47000, Pakistan.
⁹ Department of Chemistry, University of Poonch Rawalakot AJK, Pakistan.
¹⁰ Medical Research Core Facility and Platforms (MRCFP), King Abdullah International Medical Research Center/ King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), NGHA, Riyadh 11426, Saudi Arabia.
¹¹ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.

PMID: 32200327
DOI: 10.1016/j.bioorg.2020.103745

Abstract

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.

Keywords: Acetohydrazide; Molecular docking; SAR; Synthesis; Thymidine phosphorylase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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 Simulation
Molecular Structure
Recombinant Proteins / metabolism
Structure-Activity Relationship
Thymidine Phosphorylase / antagonists & inhibitors*
Thymidine Phosphorylase / metabolism

Substances

Enzyme Inhibitors
Hydrazines
Indoles
Recombinant Proteins
indole
Thymidine Phosphorylase
acetylhydrazine