Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles

  • Eur J Med Chem. 2020 Dec 1;207:112802. doi: 10.1016/j.ejmech.2020.112802.
Andrea Bistrović Popov  1 ,  Luka Krstulović  2 ,  Sanja Koštrun  3 ,  Dubravko Jelić  4 ,  Ana Bokulić  4 ,  Marijana Radić Stojković  5 ,  Iva Zonjić  5 ,  Martin C Taylor  6 ,  John M Kelly  6 ,  Miroslav Bajić  2 ,  Silvana Raić-Malić  7
Affiliations
  • 1. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev Trg 20, HR-10000, Zagreb, Croatia.
  • 2. Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, HR-10000, Zagreb, Croatia.
  • 3. Fidelta Ltd., Prilaz Baruna Filipovića 29, HR-10000, Zagreb, Croatia. Electronic address: [email protected].
  • 4. Fidelta Ltd., Prilaz Baruna Filipovića 29, HR-10000, Zagreb, Croatia.
  • 5. Division of Organic Chemistry and Biochemistry, Laboratory for Biomolecular Interactions and Spectroscopy, Ruđer Bošković Institute, Bijenička 54, HR-10000, Zagreb, Croatia.
  • 6. Department of Infection Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
  • 7. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev Trg 20, HR-10000, Zagreb, Croatia. Electronic address: [email protected].
PMID: 32927230 DOI: 10.1016/j.ejmech.2020.112802
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.

Keywords
ADME; DNA binding; Imidazoline-substituted benzimidazole; Trypanosoma brucei.
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