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

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

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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