Popov, Andrea Bistrović; Krstulović, Luka; Koštrun, Sanja; Jelić, Dubravko; Bokulić, Ana; Stojković, Marijana Radić; Zonjić, Iva; Taylor, Martin C; Kelly, John M; Bajić, Miroslav; +1 more... Raić-Malić, Silvana; (2020) Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles. European journal of medicinal chemistry, 207. 112802-. ISSN 0223-5234 DOI: https://doi.org/10.1016/j.ejmech.2020.112802
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Abstract
Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a-18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a-18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.
Item Type | Article |
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Faculty and Department | Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
PubMed ID | 32927230 |
Elements ID | 151131 |
Official URL | http://dx.doi.org/10.1016/j.ejmech.2020.112802 |
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Filename: Popov-etal-2020-Design-synthesis-antitrypanosomal-activity-dna.pdf
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