Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes

Avninder S Bhambra; Mark Edgar; Mark R J Elsegood; Yuqi Li; George W Weaver; Randolph R J Arroo; Vanessa Yardley; Hollie Burrell-Saward; Vladimir Krystof

doi:10.1016/j.ejmech.2015.11.043

Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes

Eur J Med Chem. 2016 Jan 27:108:347-353. doi: 10.1016/j.ejmech.2015.11.043. Epub 2015 Nov 30.

Authors

Avninder S Bhambra¹, Mark Edgar², Mark R J Elsegood³, Yuqi Li², George W Weaver⁴, Randolph R J Arroo⁵, Vanessa Yardley⁶, Hollie Burrell-Saward⁶, Vladimir Krystof⁷

Affiliations

¹ School of Allied Health Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK. Electronic address: abhambra@dmu.ac.uk.
² Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK.
³ Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK. Electronic address: m.r.j.elsegood@lboro.ac.uk.
⁴ Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK. Electronic address: g.w.weaver@lboro.ac.uk.
⁵ Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
⁶ London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
⁷ Palacky University & Institute of Experimental Botany, 11 783 71 Olomouc, Czech Republic.

PMID: 26698538
DOI: 10.1016/j.ejmech.2015.11.043

Abstract

Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 μM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.

Keywords: Antitrypanosomal activity; Benzothiophenes; Fluorinated drugs; Human African Trypanosomiasis; Sleeping sickness; Trypanosoma brucei rhodesiense.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiprotozoal Agents / chemical synthesis*
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
Structure-Activity Relationship
Thiophenes / chemical synthesis*
Thiophenes / chemistry
Thiophenes / pharmacology*
Trypanosoma brucei rhodesiense / drug effects*

Substances

Antiprotozoal Agents
Thiophenes