Design, synthesis, and biological activities of closantel analogues: structural promiscuity and its impact on Onchocerca volvulus

J Med Chem. 2011 Jun 9;54(11):3963-72. doi: 10.1021/jm200364n. Epub 2011 May 12.

Abstract

Onchocerciasis, or river blindness, is a neglected tropical disease that affects more than 37 million people worldwide, primarily in Africa and Central and South America. We have disclosed evidence that the larval-stage-specific chitinase, OvCHT1, may be a potential biological target for affecting nematode development. On the basis of screening efforts, closantel, a known anthelmintic drug, was discovered as a potent and highly specific OvCHT1 inhibitor. Originally, closantel's anthelmintic mode of action was believed to rely solely on its role as a proton ionophore; thus, the impact of each of its biological activities on O. volvulus L3 molting was investigated. Structure-activity relationship studies on an active closantel fragment are detailed, and remarkably, by use of a simple salicylanilide scaffold, compounds acting only as protonophores or chitinase inhibitors were identified. From these data, unexpected synergistic protonophore and chitinase inhibition activities have also been found to be critical for molting in O. volvulus L3 larvae.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chitinases / antagonists & inhibitors*
  • Chitinases / chemistry
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells
  • Filaricides / chemical synthesis*
  • Filaricides / chemistry
  • Filaricides / pharmacology*
  • HEK293 Cells
  • Haplorhini
  • Humans
  • Ionophores / pharmacology
  • Larva / drug effects
  • Molecular Structure
  • Molting / drug effects
  • Onchocerca volvulus / drug effects*
  • Onchocerca volvulus / enzymology
  • Onchocerca volvulus / growth & development
  • Onchocerciasis / drug therapy
  • Onchocerciasis / parasitology
  • Onchocerciasis, Ocular / drug therapy
  • Onchocerciasis, Ocular / parasitology
  • Protons
  • Salicylanilides / chemical synthesis*
  • Salicylanilides / chemistry
  • Salicylanilides / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Filaricides
  • Ionophores
  • Protons
  • Salicylanilides
  • Chitinases
  • closantel