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Synthesis, antiproliferative evaluation and DNA/RNA binding study of novel amidino-substituted phenylene-bis(benzazoles)

In the field of drug discovery and development, biologically important heterocyclic molecules known as “privileged structures” play an important role as promising future drug candidates, because of their versatile binding properties for different biotargets. In continuation of our recent research in the synthesis and evaluation of antiproliferative activities of amidino- substituted 2-arylbenzazole derivatives [1, 2], we present here a series of twelve novel amidino- substituted phenylene-bis(benzazoles), differing in heteroaromatic scaffolds as well as in type of amidine moiety. The synthesis of 1, 3- and 1, 4-phenylene bis- benzothiazole, benzimidazole and benzoxazole functionalized with unsubstituted and 2- imidazolinyl amidine moiety were carried out by condensation reaction of amidino-substituted 2- aminothiophenols, 2-aminophenols or o- phenylenediamines with 1, 3- and 1, 4-phenylene dicarboxylic acids. Antiproliferative evaluations of compounds were performed in vitro on several human tumour cell lines (LN-229, Capan-1, HCT-116, NCI-H460, DND-41, HL-60, K-562, Z-138). It was observed that the antiproliferative activity strongly depends on heteroaromatic scaffolds, as well as on type of amidine moiety. The 2- imidazolinyl-substituted 1, 3-phenylene- bisbezoxazole and bisbenzothizole exhibited the highest activity and inhibit tumour cell proliferation (IC50) in submicromolar concentration on almost all tested cell lines. Several compounds have been further tested for their DNA/RNA binding ability using UV/Vis (thermal denaturation), fluorescence and circular dichroism (CD) spectroscopy with the aim of investigating possible mechanisms of action.

synthesis ; amidines ; benzazoles ; antiproliferative activity ; DNA/RNA binding

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