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Updated: Oct 29, 2026

In Vitro Chemical Mapping of G-Quadruplex DNA Structures by Bis-3-Chloropiperidines
Published on: May 12, 2023
Novel amidino-substituted phenylene-bis(benzazoles): Design, synthesis, biological evaluation and DNA binding
Lucija Ptiček1, Anja Beč1, Iva Zonjić2
1University of Zagreb Faculty of Textile Technology, Department of Applied Chemistry, Prilaz Baruna Filipovića 28a, Zagreb, 10000, Croatia.
Abstract:
A series of symmetrical amidino-substituted phenylene-bis(benzazoles) incorporating benzoxazole, benzothiazole and benzimidazole scaffolds was designed to explore the influence of the heteroaromatic core, substitution pattern and amidine type on antiproliferative and antitrypanosomal activity. Distinct structure-activity relationships were observed for the two biological activity profiles. Antiproliferative activity strongly depended on both the heteroaromatic scaffold and the nature of the amidine moiety. Among the investigated series, bis(benzoxazoles) showed the highest potency, with C-6 imidazolinyl derivatives 7da and 7 db displaying submicromolar inhibitory activity across a panel of human cancer cell lines (EC50 = 0.06-2.5 μM). Evaluation in PBMCs indicated cancer cell selectivity, while cell cycle analysis of the most active derivatives revealed G2/M phase accumulation. In contrast, antitrypanosomal activity against bloodstream-form Trypanosoma brucei followed a different SAR profile, with several derivatives showing pronounced potency and favourable selectivity indices. In particular, the benzoxazole derivative 7 ab bearing an unsubstituted amidine exhibited excellent potency and selectivity (EC50 = 0.044 μM, SI = 920), while the benzothiazole derivative 3aa also demonstrated strong activity (EC50 = 0.09 μM, SI = 325). In the benzimidazole series, the imidazolinyl derivative 9ba showed a highly favourable profile (EC50 = 0.05 μM, SI = 675). Biophysical studies revealed that 9ba exhibits high affinity toward AT-rich nucleic acid structures, including triplex DNA and DNA:RNA hybrids. Integration of biological and biophysical data indicates that nucleic acid recognition may contribute to the biological activity of this series. Overall, the distinct SAR profiles identified 7 ab as the most promising antitrypanosomal lead for further optimization towards the development of potent and selective antitrypanosomal agents.
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