Abstract
Natural metabolites with their specific bioactivities are being considered as a potential source of materials for pharmacological studies. In this study, we successfully isolated and identified five known clerodane diterpenes, namely 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (1), 16-hydroxy-cleroda-3,13-dien-15-oic acid (2), 16-hydroxy-cleroda-4(18),13-dien-16,15-olide (3), 3α,16α-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (4), and 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (5) from the methanolic extract of seeds of Polyalthia longifolia. Initially, all the isolated metabolites were investigated for COX-1, COX-2, and 5-LOX inhibitory activities using the standard inhibitory kits. Of which, compounds 3, 4, and 5 exhibited to be potent COX-1, COX-2, and 5-LOX inhibitors with the IC50 values similar or lower to those of the reference drugs. To understand the underlying mechanism, these compounds were subjected to molecular docking on COX-1, COX-2, and 5-LOX proteins. Interestingly, the in silico study results were in high accordance with in vitro studies where compounds 3, 4, and 5 hits assumed interactions and binding pattern comparable to that of reference drugs (indomethacin and diclofenac), as a co-crystallized ligand explaining their remarkable dual (COX/LOX) inhibitor actions. Taken together, our findings demonstrated that compounds 3, 4, and 5 functioned as dual inhibitors of COX/5-LOX and can contribute to the development of novel, more effective anti-inflammatory drugs with minimal side-effects.
Highlights
Cyclooxygenases (COX-1/2) and lipoxygenases (LOX) are well-recognized as pro-inflammatory enzymes as well as vital enzymes in the metabolic pathway of arachidonic acid1
All of these compounds have been earlier reported from P. longifolia, it was the first time they were isolated from the seeds of this species
Based on the previous reports on the anti-inflammatory properties of the extracts of P. longifolia, we investigated the anti-inflammatory activities of these compounds in vitro
Summary
Cyclooxygenases (COX-1/2) and lipoxygenases (LOX) are well-recognized as pro-inflammatory enzymes as well as vital enzymes in the metabolic pathway of arachidonic acid1 These enzymes are essential for the physiological production of eicosanoids, including leukotrienes, prostaglandins, and thromboxane, that primarily cause inflammation. It is noteworthy that COX/5-LOX co-inhibition potentially reduces side effects on the cardiovascular and gastrointestinal tract while retaining the primary activity of COX-1/2 inhibitors With this aim, darbufelone and licofelone were first designed and clinically used as a dual COX/5-LOX inhibitory anti-inflammatory drugs. We first isolated and identified the metabolites present in methanolic extracts of seeds of P. longifolia Afterward, these metabolites were screened for their potential COX-1/2 and 5-LOX dual inhibitory activities by performing in vitro experiments. Their dual inhibitory activity and binding mode were investigated in silico using Schrodinger suite 2020-2
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.