Synthesis, crystal structures and electronic properties of isomers of chloro-pyridinylvinyl-1H-indoles

Laurence Moineaux, Sophie Laurent, Jérémy Reniers, Eduard Dolusic, Moreno Galleni, Jean-Marie Frère, Bernard Masereel, Raphaël Frédérick, Johan Wouters

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Abstract

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray diffraction. The solubility of the molecules also was determined experimentally. The molecular electrostatic potentials and dipole moments of the three isomers were calculated by ab initio quantum mechanics (HF/6-311G). The single crystal X-ray analyses reveal non-planar structures. This non-coplanarity is retained during docking of the compounds into a model of hTDO, the molecular target of this series. The position of the Cl atom does not significantly affect the electronic delocalization. Nevertheless, the position of the Cl atom produces a local variation of bond lengths inducing different dipole moments for these isomers. Variations in dipole moments are consistent with the different melting points and crystal packings. Differences in aqueous solubilities are best explained by subtle changes in H-bonds resulting from different accessibilities of the indole NH's due to steric effects of the Cl substituent. The non-coplanarity plays an important role in the crystalline packing of the molecules in contrast to the position of the Cl. This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity. © 2012 Elsevier Masson SAS. All rights reserved.

Original languageEnglish
Pages (from-to)95-102
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume54
DOIs
Publication statusPublished - 1 Aug 2012

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Keywords

  • Chloro-3-(2-pyridin-3-ylvinyl)-1H-indole
  • Crystal structure
  • Human tryptophan 2,3-dioxygenase
  • Isomer
  • Physico-chemical properties

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