Naslov
Eco-friendly synthesis, in vitro anti- proliferative evaluation and 3D-QSAR analysis of a novel series of monocationic 2- aryl/heteroaryl-substituted 6-(2- imidazolinyl)benzothiazole mesylates

Autori
Racané, Livio ; Ptiček, Lucija ; Sedić, Mirela ; Grbčić, Petra ; Kraljević Pavelić, Sandra ; Bertoša, Branimir ; Sović, Irena ; Karminski-Zamola, Grace

Izvornik
Molecular diversity (1381-1991) 22 (2018), 3; 723-741

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
heterocycles, benzothiazoles, eco-friendly synthesis, anti-proliferative activity, 3D-QSAR modelling

Sažetak
Herein, we describe the synthesis of twenty-one novel water soluble monocationic 2- aryl/heteroaryl-substituted 6-(2- imidazolinyl)benzothiazole mesylates 3a-3u and present the results of their anti-proliferative assays. Efficient syntheses were achieved by three complementary simple two-step synthetic protocols based on the condensation reaction of aryl/heteroaryl carbaldehydes or carboxylic acid. We developed an eco-friendly synthetic protocol using glycerol as green solvent, particularly appropriate for the condensation of thermally and acid sensitive heterocycles such as furane, benzofurane, pyrrole and indole. Screening of anti-proliferative activity was performed on four human tumor cell lines in vitro including pancreatic cancer (CFPAC-1), metastatic colon cancer (SW620), hepatocellular carcinoma (HepG2) and cervical cancer (HeLa), as well as in normal human fibroblast cell lines. All tested compounds showed strong to moderate anti-proliferative activity on tested cell lines depending on the structure containing aryl/heteroaryl moiety coupled to 6-(2-imidazolinyl)benzothiazole moiety. The most potent cytostatic effects on all tested cell lines with IC50 values ranging from 0.1 to 3.70 μM were observed for benzothiazoles substituted with naphtalene-2-yl 3c, benzofuran-2-yl 3e, indole-3-yl 3j, indole- 2-yl 3k, quinoline-2-yl 3s, and quinoline-3-yl 3t and derivatives substituted with phenyl 3a, napthalene-1-yl 3b, benzothiazole-2-yl 3g, benzothiazole-6-yl 3h, N-methylindole-3-yl 3l, benzimidazole-2-yl 3n, benzimidazole-5(6)-yl 3o, and quinolone-4-yl 3u with IC50 values ranging from 1.1 μM to 29.1 μM. Based on obtained anti-proliferative activities, 3D-QSAR models for five cell lines were derived. Molecular volume, molecular surface, the sum of hydrophobic surfaces areas, molecular mass and possibility of making dispersion forces were identified by QSAR analyses as molecular properties that are positively correlated with anti-proliferative activity, while compound’s capability to accept H-bond was identified as a negatively correlated property. Comparison of molecular properties identified for different cell lines enabled assumptions about similarity of mode of action through which anti- proliferative activities against different cell lines are accomplished. Novel compounds that are predicted to have enhaced activities in comparison with herein presented ones were designed using 3D-QSAR analysis as guideline.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA