@article{fdi:010073808,
  title = {{N}ovel 8-nitroquinolin-2(1{H})-ones as {NTR}-bioactivated antikinetoplastid molecules : synthesis, electrochemical and {SAR} study},
  author = {{P}edron, {J}. and {B}oudot, {C}. and {F}lutter, {S}. and {B}ourgeade-{D}elmas, {S}andra and {S}tigliani, {J}. {L}. and {S}ournia-{S}aquet, {A}. and {M}oreau, {A}. and {B}outet-{R}obinet, {E}. and {P}aloque, {L}. and {M}othes, {E}. and {L}aget, {M}. and {V}endier, {L}. and {P}ratviel, {G}. and {W}yllie, {S}. and {F}airlamb, {A}. and {A}zas, {N}. and {C}ourtioux, {B}. and {V}alentin, {A}. and {V}erhaeghe, {P}.},
  editor = {},
  language = {{ENG}},
  abstract = {{T}o study the antiparasitic 8-nitroquinolin-2(1{H})-one pharmacophore, a series of 31 derivatives was synthesized in 1-5 steps and evaluated in vitro against both {L}eishmania infantum and {T}rypanosoma brucei brucei. {I}n parallel, the reduction potential of all molecules was measured by cyclic voltammetry. {S}tructure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by {X}-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 {V} in comparison with 8-nitroquinoline). {W}ith the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from -1.1 to -0.45 {V}) was designed and provided a list of suitable molecules to be synthesized and tested. {T}his approach highlighted that, in this series, only substrates with a redox potential above -0.6 {V} display activity toward {L} infantum. {N}evertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in {T}.b. brucei. {C}ompound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human {H}ep{G}2 cell line. {C}ompound 22 is selectively bioactivated by the type {I} nitroreductases ({NTR}1) of {L}. donovani and {T}. brucei brucei. {M}oreover, despite being mutagenic in the {A}mes test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. {P}reliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.},
  keywords = {{A}nti-kinetoplastids ; {L}eishmania ; {T}rypanosoma ; 8-{N}itroquinolin-2(1{H})-one ; {N}itroreductases ; {E}lectrochemistry},
  booktitle = {},
  journal = {{E}uropean {J}ournal of {M}edicinal {C}hemistry},
  volume = {155},
  numero = {},
  pages = {135--152},
  ISSN = {0223-5234},
  year = {2018},
  DOI = {10.1016/j.ejmech.2018.06.001},
  URL = {https://www.documentation.ird.fr/hor/fdi:010073808},
}