Synthesis, docking study and relaxant effect of 2-alkyl and 2-naphthylchromones on rat aorta and guinea-pig trachea through phosphodiesterase inhibition Fernando Rodríguez-Ramos a,⇑ , Andrés Navarrete b , Martín González-Andrade c , Carlos Alarcón a , Alejandro Aguilera-Cruz a , Adelfo Reyes-Ramírez a,d,⇑ a Unidad Multidisciplinaria de Investigación Experimental, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, México DF 09230, Mexico b Facultad de Química, Departamento de Farmacia. Universidad Nacional Autónoma de México, México DF 04510, Mexico c Instituto Nacional de Medicina Genómica, Secretaria de Salud, México DF 14610, Mexico d Instituto de Química, Universidad Nacional Autónoma de México, México DF 04510, Mexico article info Article history: Available online 25 July 2013 Keywords: Chromones Vasorelaxant effect Bronchorelaxant effect Rat aorta Guinea-pig trachea PDE inhibition Docking study abstract Chromone (4), which form the base structure of various flavonoids isolated as natural products, is capable of relaxing smooth muscle. This is relevant to the treatment of high blood pressure, asthma and chronic obstructive pulmonary disease. The former disorder involves the contraction of vascular smooth muscle (VSM), and the latter two bronchoconstriction of airway smooth muscle (ASM). One of the principal mechanisms by which flavonoids relax muscle tissue is the inhibition of phosphodiesterases (PDEs), pres- ent in both VSM and ASM. Therefore, a study was designed to analyze the structure–activity relationship of chromone derivatives in vaso- and bronchorelaxation through the inhibition of PDE. Docking studies showed that these chromones bind at the catalytic site of PDEs. Consequently, we synthesized analogs of chromones substituted at position C-2 with alkyl and naphthyl groups. These compounds were synthe- sized from 2-hydroxyacetophenone and acyl chlorides in the presence of DBU and pyridine, modifying the methodology reported for the synthesis of 3-acylchromones by changing the reaction temperature from 80 to 30 °C and using methylene chloride as solvent, yielding the corresponding phenolic esters 10a–10h. These compounds were cyclized with an equivalent of DBU, pyridine as solvent, and heated at reflux temperature, yielding the chromones 11a–11h. Evaluation of the vasorelaxant effect of 4, 11a–11h on rat aorta demonstrated that potency decreases with branched alkyl groups. Whereas the EC 50 of compound 11d (substituted by an n-hexyl group) was 8.64 ± 0.39 lM, that of 11f (substituted by an isobutyl group) was 14.58 ± 0.64 lM. Contrarily, the effectiveness of the compound is directly pro- portional to the length of the alkyl chain, as evidenced by the increase in maximal effect of compound 11c versus 11d (66% versus 100%) and 11e versus 11f (60% versus 96%). With an aromatic group like naphthyl as the C-2 substituent, the effectiveness was only 43%. All compounds tested on guinea pig trachea showed less than 55% effectiveness. Compounds 4, 11a–11h were evaluated as PDE inhibitors in vitro, with 11d showing the greatest effect (73%), corroborating the importance of a long alkyl chain, which inhibits the decomposition of cGMP. Docking studies showed that the compound 11d was selective for the inhibition of PDE-5. Ó 2013 Elsevier Inc. All rights reserved. 1. Introduction Flavonoids have shown important pharmacological activity as relaxant agents of vascular smooth muscle (VSM) [1] and airway smooth muscle (ASM) [2]. One of the pharmacological action mechanisms reported for these compounds is via inhibition of phosphodiesterase (PDE) [2,3]. These effects are important in the treatment of diseases involving VSM contraction, such as arterial hypertension [3,4], as well as disorders involving ASM contraction, such as asthma and chronic obstructive pulmonary disease (COPD) [2,4]. Whereas the use of PDE-4 inhibitors is well-documented as a therapeutic alternative in the treatment of asthma and COPD [5], it is still under study for VSM contraction. There is a remarkable interest in the potential use of PDE-5 inhibitors in combination with others drugs for the treatment of systemic hypertension [6]. 0045-2068/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bioorg.2013.07.001 ⇑ Corresponding authors. Address: Facultad de Estudios Superiores Zaragoza. Unidad Multidisciplinaria de Investigación Experimental. Universidad Nacional Autónoma de México. Batalla 5 de Mayo esquina Fuerte de Loreto, Ejército de Oriente, Iztapalapa 09230, México D.F. Mexico. Fax: +52 57736330. E-mail addresses: dr.frodriguezr@comunidad.unam.mx (F. Rodríguez-Ramos), adelfo@puma2.zaragoza.unam.mx (A. Reyes-Ramírez). Bioorganic Chemistry 50 (2013) 17–25 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg