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Synthesis and activity mechanism of some novel 2-substituted benzothiazoles as hGSTP1-1 enzyme inhibitors

K Bolelli1, Y Musdal2, E Aki-Yalcin1

  • 1a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Ankara University , Ankara , Turkey.

SAR and QSAR in Environmental Research
|December 6, 2017
PubMed

Insights

Researchers identified two novel benzothiazole derivatives that inhibit human glutathione S-transferase P1-1 (hGSTP1-1), a key protein in cancer drug resistance. These compounds show promise as potential anticancer agents by targeting the hGSTP1-1 binding site.

Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Pharmacology

Background:

  • Human glutathione S-transferase P1-1 (hGSTP1-1) is frequently overexpressed in human tumors.
  • hGSTP1-1 overexpression is linked to resistance against multiple anticancer drugs, making it a significant therapeutic target.
  • Developing effective inhibitors of hGSTP1-1 is crucial for overcoming drug resistance in cancer treatment.

Purpose of the Study:

  • To synthesize and evaluate novel benzothiazole derivatives for their in vitro inhibitory activity against hGSTP1-1.
  • To identify lead compounds with significant hGSTP1-1 inhibitory potential.
  • To elucidate structure-activity relationships (SARs) and binding interactions of the lead compounds with hGSTP1-1.

Main Methods:

  • Synthesis of 12 benzothiazole derivatives.
  • In vitro screening of synthesized compounds for hGSTP1-1 inhibitory activity.
  • Generation of a HipHop pharmacophore model for SAR analysis.
  • Molecular docking studies using the CDocker method to investigate binding interactions.

Main Results:

  • Two lead compounds, #2 and #5, demonstrated significant in vitro inhibitory activity against hGSTP1-1, outperforming the reference drug etoposide.
  • Pharmacophore modeling and molecular docking revealed that lead compounds bind to the H-site of hGSTP1-1.
  • The para-substituted phenyl ring of the benzamide moiety on the benzothiazole core is critical for interaction with the active site residue Tyr108.

Conclusions:

  • Benzothiazole derivatives #2 and #5 are potent inhibitors of hGSTP1-1.
  • These compounds exert their inhibitory effect by binding to the H-site, mimicking substrate interaction.
  • Hydrophobic substitution at the para position of the phenyl ring enhances binding affinity and is essential for interaction with Tyr108.
Keywords:
AnticancerGSTsbenzothiazoledockinghGSTP1-1pharmacophore

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