New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase.

Elodie Lohou (1) , Jana Sopkova-de Oliveira Santos (1) , Pascale Schumann-Bard , Michel Boulouard (2) , Silvia Stiebing (1) , Sylvain Rault , Valérie Collot (1)

1 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
2 GMPc - Groupe Mémoire et Plasticité comportementale

Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N(1)- and N(2)-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.

Domaines: Neurosciences

Elodie Lohou, Jana Sopkova-de Oliveira Santos, Pascale Schumann-Bard, Michel Boulouard, Silvia Stiebing, et al.. New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase.. Bioorganic and Medicinal Chemistry, 2012, 20 (17), pp.5296-304. ⟨10.1016/j.bmc.2012.06.025⟩. ⟨hal-00862829⟩