TY - JOUR
T1 - Synthesis, ex vivo and in silico studies of 3-cyano-2-pyridone derivatives with vasorelaxant activity
AU - Hernández, Fernando
AU - Sánchez, Arturo
AU - Rendón-Vallejo, Priscila
AU - Millán-Pacheco, César
AU - Alcaraz, Yolanda
AU - Delgado, Francisco
AU - Vázquez, Miguel A.
AU - Estrada-Soto, Samuel
N1 - Funding Information:
This study was financed by a grant from “ Apoyo a la Mejora del Perfil Individual del profesorado de tiempo completo (Fondo para la Consolidación de las Universidades Públicas Estatales y con Apoyo Solidario Ejercicio 2009)” and Faculty of Pharmacy Budgets (FECES 2011 and 2012). F.H. thanks CONACyT for a graduate scholarship (no. 482137) M.A.V. acknowledges CONACyT (grant 168474 ) and UGto-DAIP (grant 281/13).
PY - 2013
Y1 - 2013
N2 - An efficient and simple synthesis of 3-cyano-2-pyridone derivatives (6a-f) through 3,4-dihydropyridin-2-one oxidation process is described. A greener method to synthesize 3,4-dihydropyridin-2-one has also been developed by rearranging 4H-pyran (4a-f) derivatives in aqueous medium applying H 2SO4 as the catalyst source and microwave irradiation. The vasorelaxant activity of 3-cyano-2-pyridone derivatives (6a-f) was proved on isolated thoracic aorta rat rings with and without endothelium (+E and -E, respectively) pre-contracted with noradrenaline (0.1 μM). All compounds exhibited significant concentration-dependent and endothelium-independent vasorelaxant effects being the nitro derivatives (6a and f) and compound 6d the most potent with EC50 of 7, 4.4 and 5 μM, respectively. Finally, a previously described 3D model of the central pore of human L-type calcium channel (LCC), modified to be on agreement with NCBI sequence NP-005174.2 for subunit alpha-1F isoform 1, was used to dock most active compounds. 6a, d and f lowest affinity energy structures were found docked in the same cavity conformed by IS6, IS5, IP and IIS6 helices. Nifedipine lowest energy structure was found in the cavity formed by IIS6, IIS5, IIP and IIIS6. Although nifedipine docked in a different cavity, the superposition of both, allowed us to observe that they were almost the same cavities, indicating that there exist subtle steric differences that lead to a different docking for nifedipine. All compounds docked with similar free energy of binding.
AB - An efficient and simple synthesis of 3-cyano-2-pyridone derivatives (6a-f) through 3,4-dihydropyridin-2-one oxidation process is described. A greener method to synthesize 3,4-dihydropyridin-2-one has also been developed by rearranging 4H-pyran (4a-f) derivatives in aqueous medium applying H 2SO4 as the catalyst source and microwave irradiation. The vasorelaxant activity of 3-cyano-2-pyridone derivatives (6a-f) was proved on isolated thoracic aorta rat rings with and without endothelium (+E and -E, respectively) pre-contracted with noradrenaline (0.1 μM). All compounds exhibited significant concentration-dependent and endothelium-independent vasorelaxant effects being the nitro derivatives (6a and f) and compound 6d the most potent with EC50 of 7, 4.4 and 5 μM, respectively. Finally, a previously described 3D model of the central pore of human L-type calcium channel (LCC), modified to be on agreement with NCBI sequence NP-005174.2 for subunit alpha-1F isoform 1, was used to dock most active compounds. 6a, d and f lowest affinity energy structures were found docked in the same cavity conformed by IS6, IS5, IP and IIS6 helices. Nifedipine lowest energy structure was found in the cavity formed by IIS6, IIS5, IIP and IIIS6. Although nifedipine docked in a different cavity, the superposition of both, allowed us to observe that they were almost the same cavities, indicating that there exist subtle steric differences that lead to a different docking for nifedipine. All compounds docked with similar free energy of binding.
KW - 2-Pyridones
KW - 4H-Pyrans
KW - Docking score
KW - L-type calcium channel
KW - Microwave irradiation
KW - Vasorelaxant activity
UR - http://www.scopus.com/inward/record.url?scp=84887154477&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2013.10.018
DO - 10.1016/j.ejmech.2013.10.018
M3 - Artículo
C2 - 24212125
SN - 0223-5234
VL - 70
SP - 669
EP - 676
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -