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

BOLELLİ K., Musdal Y., Aki-Yalcin E., Mannervik B., Yalcin I.

SAR AND QSAR IN ENVIRONMENTAL RESEARCH, vol.28, no.11, pp.927-940, 2017 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 28 Issue: 11
  • Publication Date: 2017
  • Doi Number: 10.1080/1062936x.2017.1402820
  • Journal Name: SAR AND QSAR IN ENVIRONMENTAL RESEARCH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.927-940
  • Keywords: Anticancer, benzothiazole, docking, hGSTP1-1, GSTs, pharmacophore, GLUTATHIONE TRANSFERASE P1-1, EFFLUX PUMP INHIBITORS, PHARMACOPHORE IDENTIFICATION, MOLECULAR DOCKING, S-TRANSFERASES, DERIVATIVES, BINDING, DNA, BENZOXAZOLES, GENERATION
  • Ankara University Affiliated: Yes

Abstract

Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of human tumours and is involved in the development of resistance to several anticancer drugs. So, it has become an important target in cancer treatment. In this study, 12 benzothiazole derivatives were synthesized and screened for their in vitro inhibitory activity for hGSTP1-1. Among these compounds, two of them (compounds #2 and #5) have been found to be the leads when compared with the reference drug etoposide. In order to analyse the structure-activity relationships (SARs) and to investigate the binding side interactions of the observed lead compounds, a HipHop pharmacophore model was generated and the molecular docking studies were performed by using CDocker method. In conclusion, it is observed that the lead compounds #2 and #5 possessed inhibitory activity on the hGSTP1-1 by binding to the H-site as a substrate in which the para position of the phenyl ring of the benzamide moiety on the benzothiazole ring is important. Substitution at this position with a hydrophobic group that reduces the electron density at the phenyl ring is required for the interaction with the H side active residue Tyr108.