title: Synthesis, crystal structures and electronic properties of isomers of chloro-pyridinylvinyl-1H-indoles.
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.
authors.affiliation: Namur Medicine & Drug Innovation Center (NAMEDIC Member of NARILIS), Laboratory of Biological and Structural Chemistry, University of Namur (FUNDP), rue de Bruxelles 61, B-5000 Namur, Belgium. Laurence.moineaux@fundp.ac.be
authors.forename: Laurence
authors.initials: L
authors.lastname: Moineaux
authors.forename: Sophie
authors.initials: S
authors.lastname: Laurent
authors.forename: Jérémy
authors.initials: J
authors.lastname: Reniers
authors.forename: Eduard
authors.initials: E
authors.lastname: Dolušić
authors.forename: Moreno
authors.initials: M
authors.lastname: Galleni
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Frère
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
mesh_terms: D000595:Amino Acid Sequence; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004583:Electrons; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007536:Isomerism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D043367:Ralstonia / Q000201:enzymology; D055672:Static Electricity; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D014366:Tryptophan Oxygenase