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

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.

Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli.

The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.

Pharmacophore generation of 2-substituted benzothiazoles as AdeABC efflux pump inhibitors in A. baumannii.

RND family efflux pumps are important for multidrug resistance in Gram-negative bacteria. To date no efflux pump inhibitors for clinical use have been found, so developing the specific inhibitors of this pump system will be beneficial for the treatment of infections caused by these multidrug-resistant pathogens. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combination with ciprofloxacin (CIP) against the RND family efflux pump AdeABC overexpressor Acinetobacter baumannii SbMox-2 strain. The results indicated that the BSN compounds did not have antimicrobial activity when tested alone. However, if they were applied in combination with CIP, it was observed that the antibiotic had antimicrobial activity against the tested pathogen, possessing a minimum inhibitory concentration value that could be utilized in clinical treatment. A 3D-common features pharmacophore model was applied by using the HipHop method and the generated pharmacophore hypothesis revealed that the hydrogen bond acceptor property of nitrogen in the thiazole ring and the oxygen of the amide substituted at the second position of the benzothiazole ring system were significant for binding to the target protein. Moreover, three hydrophobic aromatic features were found to be essential for inhibitory activity.

Micro-Raman, mid-IR, far-IR and DFT studies on 2-[4-(4-fluorobenzamido)phenyl]benzothiazole.

Molecular structure of 2-[4-(4-Fluorobenzamido)phenyl]benzothiazole was determined by quantum chemical calculations. MidIR and FarIR spectra were recorded at room temperature, with 4 cm(-1) resolution in the 4000-400 cm(-1) and 700-30 cm(-1) regions, respectively for the first time. Raman spectrum was recorded in the 4000-100 cm(-1) range. Optimized molecular structure and vibrational wavenumbers of the compound in its ground state have been calculated by using Density Functional Theory using B3LYP functional with 6-311++G(d,p) basis set. Vibrational wavenumbers were seen to be in good agreement with the experimental IR data. Furthermore, assignments of each vibrational mode were interpreted in terms of potential energy distributions in detail.

QSAR and pharmacophore analysis on amides against drug-resistant S. aureus.

Considering the worth of developing new antibacterial agents against drug-resistant Stapylococcus aureus, the present study explores the structure-activity relationships analysis of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives using classical QSAR and 3D-common-feature pharmacophore hypothese approaches. QSAR analysis revealed that the compounds possessing a methylene group between the phenyl and the carboxyamido moiety played a role for decreasing the activity. On the other side, substituent effects on position R1 was found important for the activity and holding a substituent possessing a minimum width property on this position like as alkyl groups enhanced the activity. Moreover, substituting position R3 with a group enhancing the electron-donor capability of the phenolic ring system increased the potency. 3D-common-feature pharmacophore approach considered that the conformational properties of the compounds were important for the activity against drug-resistant S. aureus and compounds possessing a benzamide moiety rather than phenylacetamide structure increased the activity. Furthermore, holding NO2 and OH groups on the phenyl ring attached to the benzamide moiety was important for improving the potency against drug-resistant S. aureus.