Med Chem Res DOI 10.1007/s00044-017-2055-y MEDICINAL CHEMISTR Y RESEARCH ORIGINAL RESEARCH Relaxant effect of structurally related ﬂavonoids on isolated tracheal rat rings: a SAR study Angélica Flores-Flores 1 ● Sergio Hidalgo-Figueroa 1 ● Rafael Villalobos-Molina 2 ● Maximiliano Ibarra-Barajas 2 ● Blanca Bazán-Perkins 3 ● Gabriel Navarrete-Vázquez 1 ● Samuel Estrada-Soto 1 Received: 7 June 2017 / Accepted: 28 August 2017 © Springer Science+Business Media, LLC 2017 Abstract In the search for potential new antiasthmatic drugs, the ex vivo relaxing effect and structural activity relationship (SAR) studies of a series of ten structurally related ﬂavonoids were established. Also, glycosylated and prenylated ﬂavonoids were included in this study in order to explore their relaxant effect. All ﬂavonoids studied showed a signiﬁcant relaxant effect on the contraction induced by carbachol (CCh) 1 μM on tracheal rat rings, with the exception of isoprenylated and glycosylated derivatives. Results indicated that the ﬂavone scaffold or their 6- substituted or 7-substituted positions, exhibited best relax- ant activity, being ﬂavone (1), 6-hydroxyﬂavone (2), 6- aminoﬂavone (3), and 7-hydroxyﬂavone (6) the most active compounds, even more than the positive control (Theo- phylline). On the other hand, SAR analysis suggested that the presence of hydrogen-bond donor and acceptor sub- stituents in position 6- or 7- in the ﬂavone core, or the 2 and 3 double bond, and the increasing presence of hydroxyl groups in positions 4′-, 5′-, 6′-, and 6- could enhance the ex vivo relaxant effect of the ﬂavonoids studied. Derived from SAR analysis, a pharmacophore mapping was pro- posed, taking into account the structure of 6-hydroxy- ﬂavone, in order to have the scaffold to show the best ex vivo relaxant activity. Keywords Antiasthmatic drug ● Flavonoids ● 6- hydroxyﬂavone ● Relaxant effect Introduction The Global Initiative for Asthma (GINA) deﬁnes it as a chronic inﬂammatory disorder of the airways. Chronically inﬂamed airways are hyperresponsive; they become obstructed and airﬂow is limited by reversed bronchocon- striction, mucus plugs, and increased inﬂammation when the airways are exposed to various risk factors such as environmental (GINA 2017). Currently, asthma affects approximately 300 million persons worldwide, and in Mexico, 4940 deaths were caused by asthma (GINA 2017; Shrimanker and Pavord 2017). Symptoms of asthma are treated with anti-inﬂammatory and bronchodilator inhaled agents (GINA 2017); however, with these treatments there are many adverse effects and/or symptoms that are not well controlled (Land and Wang 2017). In this context, plants especially those with ethnopharmacological uses have been the primary source for early drug discovery. Furthermore, many bioactive compounds have been isolated from these or have served as a prototypes to develop new molecules of therapeutic interest (Taur and Patil 2011; Cragg and New- man 2013). In recent years, there has been increasing interest in the study of ﬂavonoids, which are plant * Gabriel Navarrete-Vázquez gabriel_navarrete@uaem.mx * Samuel Estrada-Soto enoch@uaem.mx 1 Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico 2 UBIMED, FES-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla Estado de México 54090, Mexico 3 Departamento de Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, Ciudad de México 14080, Mexico Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00044-017-2055-y) contains supplementary material, which is available to authorized users.