INDOLE-PYRIDO[2,3-d]PYRIMIDINE HYBRIDS: THREE-COMPONENT SYNTHESIS AND BINDING STUDIES AGAINST DOPAMINERGIC RECEPTORS

M. NOGUERAS; J.COBO; S, ANDUJAR; D. CORTES; ENRIZ R D

Lisboa

Congreso; 19th European Symposium on Organic Chemistry; 2015

Pteridine is the heterocyclic core presents in important biological metabolites such folic acid or pterin; deazapteridine analogs, such pyrido[2,3-d]pyrimidine compounds exhibit relevant enzymatic activity along with for example antiproliferative propierties, such as dihydrofolate reductase (DHFR) inhibition, [1] being used e.g. in the treatment of cancer.[2,3] We are here reporting the MCR?s between corresponding 4-aminopyrimidine 1a or 1b, 3-(1H-indol-3-yl)-3-oxopropanenitrile 2 and aromatic aldehydes 3, both at classical reflux in acetic acid and under free-solvent MWI-assisted with InCl3 as a catalyst, to afford the hybrids 4 and 5, with better results for these last environmentally friendlier conditions.Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 Dopaminergic Receptor and establish the structure activity relationship (SAR) as dopaminergic agents on three of those compounds, displaying a remarkable selectivity for D2 receptor and low affinity for D1 receptor. A molecular modelling study was carried out, combining both Molecular Dynamics simulations with DFT calculations, to provide a clear picture of the ligand binding interactions from a structural and energetic point of view. Therefore, it is likely that compounds behave as D2 DR agonist since serine residues cluster are crucial for agonist binding and receptor activation.Acknowledgements: DV and JT acknowledge for the financial support due by the Colombian Institute for Science and Research (COLCIENCIAS). JC and MN thank the financial support from the Consejería de Economía, Innovación y Ciencia (Junta de Andalucía) and Universidad de Jaén.References:[1]. Kurumurthy, C.; Sambasiva, R.P.; Veera, S.B.; Santhosh, K.G.; Shanthan, R.P.; Narsaiah, B.; Velatooru, L.R.; Pamanji, R.;Venkateswara, R.J. Eur. J. Med. Chem. 2011, 46, 3462-3468.[2]. Castex, C.; Lalanne, C.; Mouchet, P.; Lemaire, M.; Lahana, R. Tetrahedron. 2005, 61, 803?812[3]. Zink, M.; Lanig, H.; Troschütz, R. Eur. J. Med. Chem. 2004, 39, 1079?1088.