Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites
Há Thi Nguyen, Thien‐Y Vu, Vishala Chandi, Haritha Polimati, Vinay Bharadwaj Tatipamula
Abstract
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 IC 50 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.