In vitro COX-1 and COX-2 enzyme inhibitory activities of iridoids from Penstemon barbatus, Castilleja tenuiflora, Cresentia alata and Vitex mollis M. Ángeles Ramírez-Cisneros a , María Yolanda Rios a,⇑ , A. Berenice Aguilar-Guadarrama a , Praveen P. N. Rao b , Rola Aburto-Amar c , Verónica Rodríguez-López c a Centro de Investigaciones Químicas, IICBA, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico b School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Ave W., Waterloo, ON N2L3G1, Canada c Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico article info Article history: Received 24 July 2015 Revised 25 August 2015 Accepted 27 August 2015 Available online xxxx Keywords: Iridoids Cyclooxygenase-2 Cyclooxygenase-1 Non-steroidal anti-inflammatory drugs Prostaglandin abstract A group of sixteen iridoids isolated from plants used as anti-inflammatory remedies in Mexican folk medicine were evaluated for their potential to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. From these assays, loganic acid (10) was identified as the most promising compound with both COX-1 (36.0 ± 0.6%) and COX-2 (80.8 ± 4.0%) inhibition at 10 lM. Compound 10 shows a better inhibition against the COX-2 enzyme. Other iridoids tested in the present study showed weak or no inhibition against these enzymes. Furthermore, herein are presented key interactions of iridoid 10 with COX-1 and COX-2 enzymes through molecular docking studies. These studies suggest that 10 exhibits anti-inflammatory activity due to COX inhibition. Ó 2015 Published by Elsevier Ltd. Inflammation is present in several disorders and diseases like atherosclerosis, diabetes and cancer. 1–3 Thus, anti-inflammatories represent one of the most used groups of compounds to treat many clinical conditions. 3–5 Historically, people were dependent on folk- loric medicine to treat these complaints. Hence, the research on plant species and its secondary metabolites is a promising tool. 6,7 In this regard, iridoids represent a class of novel natural products with anti-inflammatory activity that have been purified by bioas- say-guided studies. 8 Iridoids are bicyclic monoterpenes containing a pyran ring in their structure. They can include a sugar moiety, typically b-glucose, linked through b-hemiacetal bond to C1. Fami- lies rich in this type of monoterpene are Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae and Verbenaceae. 8 Cyclooxygenase-1 (COX-1) is an enzyme expressed constitu- tively in almost all cells and has great ubiquity in colon, kidney, spleen, stomach, liver, lungs, heart and brain. This explains the broad spectrum of biological responses and its cytoprotective properties, mainly in the gastrointestinal tract. In contrast, Cyclooxygenase-2 (COX-2) is not expressed constitutively in cells, but can be induced by cytokines, growth factors and endotox- ins. 9,10 Both COX enzymes produce prostaglandins (PGs) which are involved in vascular, pain and inflammatory processes. By acting on arachidonic acid they produce PGG2 that is converted into PGH2. This PGH2 is transformed to one of five final metabolites, PGE2, PGD2, PGF2a, PGI2 or TxA2, depending on the tissue. 10 Therefore, it is suggested that COX-2 is the target for anti-inflammatory responses. In the present study, sixteen iridoids isolated from four species (Penstemon barbatus Kunth, Castilleja tenuiflora Kunth, Cresentia alata Kunth and Vitex mollis Kunth) were evaluated for their inhibi- tory activity against COX-1 and COX-2 (Table S1), with the purpose of establishing their potential as anti-inflammatory agents. Aerial parts of Penstemon barbatus, the whole plants of Castilleja tenuiflora, the leaves of Cresentia alata (all three species belonging to Bignoniaceae) and the leaves of Vitex mollis (Verbenaeae) were collected in different localities from Morelos state, Mexico: Cuernavaca, Huitzilac, Sierra de Huautla and Tepalcingo, respectively. A voucher specimen for each plant was deposited at Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México in two herbariums. Firstly, at CIBYC Herbarium with voucher numbers Bonilla-585 (P. barbatus) and Bonilla-616 (C. tenuiflora) and at HUMO Herbarium with voucher numbers 14111 (C. alata) and 19052 (V. mollis). Compounds were isolated by open column chromatography (CC). The isolation procedures and purity of compounds were http://dx.doi.org/10.1016/j.bmcl.2015.08.075 0960-894X/Ó 2015 Published by Elsevier Ltd. ⇑ Corresponding author. Tel.: +52 777 329 7000; fax: +52 777 329 7997. E-mail address: myolanda@uaem.mx (M.Y. Rios). Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Please cite this article in press as: Ramírez-Cisneros, M. Á. ; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j. bmcl.2015.08.075