Synthesis, SAR elucidations and molecular docking study of newly designed isatin based oxadiazole analogs as potent inhibitors of thymidine phosphorylase

Javid MT 1 , Rahim F 2 , Taha M 3 , Nawaz M 1 , Wadood A 4 , Ali M 5 Show all authors , Mosaddik A 6 , Shah SAA 7 , Farooq RK 8

Affiliations 

  • 1 Depatment of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan
  • 2 Depatment of Chemistry, Hazara University, Mansehra 21300, Khyber Pakhtunkhwa, Pakistan. Electronic address: [email protected]
  • 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. Electronic address: [email protected]
  • 4 Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
  • 5 UoN Chair of Oman's Medicinal Plants and Marine Natural Products, University of Nizwa, P.O. Box 33, Birkat Al Mauz, Nizwa 616, Oman
  • 6 Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
  • 7 Atta-ur-Rahman Institute for Natural Product Discovery (AuRIns), Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia; Faculty of Pharmacy, Universiti Tecknologi MARA Puncak Alam, 42300 Bandar Puncak Alam, Selangor D. E., Malaysia
  • 8 Department of Neuroscience Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia
Bioorg Chem, 2018 09;79:323-333.
PMID: 29803079 DOI: 10.1016/j.bioorg.2018.05.011

Abstract

Thymidine phosphorylase is an enzyme involved in pyrimidine salvage pathway that is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is enormously up regulated in a variety of solid tumors. Furthermore, surpassing of TP level protects tumor cells from apoptosis and helps cell survival. Thus TP is identified as a prime target for developing novel anticancer therapies. A new class of exceptionally potent isatin based oxadiazole (1-30) has been synthesized and evaluated for thymidine phosphorylase inhibitory potential. All analogs showed potent thymidine phosphorylase inhibition when compared with standard 7-Deazaxanthine, 7DX (IC50 = 38.68 ± 1.12 µM). Molecular docking study was performed in order to determine the binding interaction of these newly synthesized compounds, which revealed that these synthesized compounds established stronger hydrogen bonding network with active site of residues as compare to the standard compound 7DX.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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