Incensole derivatives from frankincense: Isolation, enhancement, synthetic modification, and a plausible mechanism of their anti-depression activity

• Published in: Bioorganic chemistry 2022-09, Vol.126, p.105900-105900, Article 105900
• Main Authors: Ur Rehman, Najeeb, Al-Shidhani, Sulaiman, Karim, Nasiara, Khan, Ajmal, Khan, Imran, Ahsan Halim, Sobia, Khan Sadozai, Sajid, Kumar Avula, Satya, Csuk, Rene, Al-Harrasi, Ahmed
• Format: Article
• Language: English
• Subjects: Anti-depression; Boswellia papyrifera; Forced swimming test; Frankincense; GABA; Incensole; Molecular docking; Tail suspension test
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105900

[Display omitted] •Different derivatives of incensole (1) and incensole acetate (2) were synthesized in the present study.•The structures of synthesized compounds were confirmed using advance spectroscopic techniques NMR and Mass Spectrometry.•Compounds 3a-e and 4a-c were investigated for their putative anti-depression activities using classical mouse models of depression of FST and TST.•The results determined that compounds 3a-e caused dose dependent reduction in immobility time compared to the vehicle control, with 4c-4e demonstrating higher potency and efficacy.•Similar results were obtained with compounds 4a-c, with 4b and 4c found to be the most potent and efficacious among the studied compounds.•Furthermore, molecular docking has predicted that compounds 3e and 4c bind at the GABA binding site of GABAA receptor in order to produce GABAergic effects. Encouraged by the potent anti-depression activities of incensole (1) and incensole acetate (2) isolated from the resin of Boswellia papyrifera in our previous work, different derivatives of 1 and 2 were synthesized in the present study. The reaction of 1 with m-CPBA afforded the mono-epoxide derivative 3a, while the same reaction with 2 led to three different epoxide derivatives 3a, 3b, and 3c. Oxidation of 1 with PCC to get compound 3b, however along with the target 3b, the reaction gave three interesting side products (3c-3e). Oxime (3b-1) resulted from the reaction of 3b with hydroxylamine hydrochloride in pyridine, while epoxidation of 2 generate three epoxide products (4a-4c). The structures of all products were unambiguously confirmed using NMR and Mass spectrometry. Compounds 3a-e and 4a-c (0.1–3 mg/kg, i.p.) demonstrated promising anti-depression activities in classical mouse models of depression of FST and TST. The results showed that compounds 3a-e and 4a-c (0.1–3 mg/kg, i.p.) caused dose dependent reduction in immobility time compared to the vehicle control, with 3c-3e and 4b-4c demonstrating higher potency and efficacy. The findings of the open field test excluded the motor effects of these compounds, thus further confirming their anti-depression activity. Preliminary investigation into their mechanism of action using GABA antagonist, PTZ and molecular docking has predicted that compounds 3e and 4c bind at the GABA binding site of GABAA receptor to produce GABAergic effects. Furthermore, the promising anti-depression potency of compounds 1 and 2 and their derivatives make them lead compounds f