title: Synthesis of azepino[4,5-b]indol-4-ones via MCR/free radical cyclization and in vitro-in silico studies as 5-Ht₆R ligands.
abstract: A series of nine new 3-acetamide-azepino[4,5-b]indol-4-ones were synthesized in two steps: (i) multicomponent reaction (Ugi-4CR/SN2) and (ii) free radical-mediated cyclization. These compounds, along with their tetrazole-based analogs, were studied in vitro to assess their binding with the 5-hydroxytryptamine type 6 receptor (5-Ht6R). The 3-acetamide-azepino[4,5-b]indol-4-ones displayed moderate affinity, whereas the 3-tetrazolylmethyl-azepino[4,5-b]indol-4-ones affinity values are lower. However, one of the 3-acetamide-azepino[4,5-b]indol-4-ones exhibited a hit value of Ki (211.2nM) to the 5-Ht6R. Minimal-energy structures of one cis-amide and its tetrazole-based analog (calculated by means of the Density Functional Theory) were analyzed to assess some interesting bioisosterism aspects. Interactions and binding energies between all products and the 5-Ht6R were calculated through in silico molecular couplings. Finally, a QSAR model was proposed using the results of the in vitro assays.
authors.affiliation: Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato C.P. 36050, Guanajuato, Mexico.
authors.forename: Angel
authors.initials: A
authors.lastname: Rentería-Gómez
authors.affiliation: Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato C.P. 36050, Guanajuato, Mexico.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Islas-Jácome
authors.affiliation: Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato C.P. 36050, Guanajuato, Mexico.
authors.forename: Erik
authors.initials: E
authors.lastname: Díaz-Cervantes
authors.affiliation: Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato C.P. 36050, Guanajuato, Mexico.
authors.forename: Tayde
authors.initials: T
authors.lastname: Villaseñor-Granados
authors.affiliation: Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato C.P. 36050, Guanajuato, Mexico. Electronic address: roblesj@ugto.mx.
authors.forename: Juvencio
authors.initials: J
authors.lastname: Robles
authors.affiliation: Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, Guanajuato C.P. 36050, Guanajuato, Mexico. Electronic address: rociogm@ugto.mx.
authors.forename: Rocío
authors.initials: R
authors.lastname: Gámez-Montaño
mesh_terms: D003500:Cyclization; D005609:Free Radicals / Q000737:chemistry*; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: D005609:Free Radicals; D007211:Indoles; D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor
keywords: Docking; Free radicals; Multicomponent reactions; QSAR; Ugi reaction