Synthesis, pharmacological and molecular docking investigations of 1,3,4-oxadiazole-5-thionyl derivatives of extracted cis-clerodane diterpenoid from Cistus monspeliensis

Two main products namely 18-hydroxy-cis-clerodan-3-ene-15-oic acid and 18-acetoxy-cis-clerodan-3-ene-15-oic acid were isolated from the extract of the plant Cistus monspeliensis. The 18-acetoxy acid converted to its mother 18-hydroxy acid in good yield. Other two 1,3,4- oxadiazole derivatives namely 5-((R)-4-((1S,2R,4aS,8aR)-5-(hydroxymethyl)-1,2,4a-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl)-2-methylbutyl)-1,3,4-oxadiazole-2(3H)-thione and 5-((R)-2-methyl-4-((1S,2R,4aS,8aR)-1,2,4a,5-tetramethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl)butyl)-1,3,4-oxadiazole-2(3H)-thione were synthesized from the obtained acid, characterized by infrared, H-1, C-13-NMR and mass spectroscopy. Their antioxidant power using the DPPH method showed interesting results compared with the reference ascorbic acid (IC50 = 16.30 mu M). Their antibacterial activity on Gram-positive bacteria Staphylococcus aureus (ATCC 33862) and Bacillus cereus (ATCC 10876), and Gram-negative bacteria Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922) showed that the resulting 1,3,4-oxadiazole thiones have interesting effects against both Gram-positive bacteria using amikacin as a positive reference. The anti-inflammatory activity investigation showed that both clerodane diterpenoid 1,3,4-oxadiazolyl-5-thionyl derivatives had higher inhibition effect on the nitric oxide production with IC50 NO values of 43.59 & PLUSMN; 1.8 and 18.64 & PLUSMN; 0.06 mu M compared to that of diclofenac (IC50 NO = 73.30 & PLUSMN; 0.40 mu M). Docking studies showed that the terpene skeleton of the starting material and both heterocycles form hydrophobic and H-bonds interactions with iNOS. The thione group of the C18-methyl oxadiazole forms a hydrogen bond with Met368, which may explain its highest anti-inflammatory activity. Graphical abstract

Automated summary

Two main products, 18-hydroxy-cis-clerodan-3-ene-15-oic acid and 18-acetoxy-cis-clerodan-3-ene-15-oic acid, were isolated from the plant Cistus monspeliensis. The 18-acetoxy acid was converted to its mother 18-hydroxy acid in good yield. The synthesized 1,3,4-oxadiazole derivatives showed interesting antioxidant and antibacterial activities, as well as higher anti-inflammatory effects compared to the reference compound.