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

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.

Benzothiazole derivatives as anticancer agents

“…The benzamide benzothiazole derivative 43 and benzamide methylbenzothiazole 44 (Figure 26) showed potent hGSTP1-1 inhibitory activities, useful in cancer chemotherapy. The SAR studies pinpointed that both these scaffold showed effective inhibition due to the presence of para -substitutions on the phenyl ring of the benzamide group 47 .…”

DESIGN OF SULFONAMIDOBENZOTHIAZOLE DERIVATIVES AS hGSTP1-1 INHIBITORS

“…Tüm bu nedenlerden dolayı son zamanlarda hGST P1-1 enzimi kanser tedavisi için bir hedef haline gelmiştir [4]. Doğada glutatyon S-transferaz aktivitesi gösteren enzimler, mitokondriyal, mikrozomal ve sitozolik olmak üzere üç alt gruptan oluşmaktadır [5,6].…”

“…Cterminal domain ise tamamen α-helikal yapılardan oluşmaktadır. Hidrofobik bağlanma bölgesi (H bölgesi) iki domain arasında olup, çoğu hidrofobik bileşik bu bölge ile etkileşmektedir (Şekil 1) [4,7,11]. Şekil 1.…”

An Efficient One‐Pot Three‐Component Synthesis of Some New 3‐(Benzo[d]thiazol‐2‐yl)‐2‐alkyl‐4(3H)‐quinazolinones Using Silica Sulfuric Acid as a Heterogeneous Catalyst

“…Therefore, several methods for the synthesis of substituted benzothiazoles and quinazolin‐4(3 H )‐ones have been reported in the literature.…”