Insights into the inhibitory activities of neolignans and diarylnonanoid derivatives from nutmeg ( Myristica fragrans Houtt.) seeds on soluble epoxide hydrolase using in vitro and in silico approaches

Abstract

Two new neolignans, myrifralignans F–G ( 14 and 18 ), four new diarylnonanoid derivatives, myrifragranones A–D ( 21 – 24 ), and 18 known compounds were isolated and structurally elucidated from nutmeg ( Myristica fragrans Houtt.) seeds. The absolute configurations of these secondary metabolites were determined using the electronic circular dichroism technique. The inhibitory potential of these isolated compounds on soluble epoxide hydrolase (sEH) was investigated for the first time. Among them, malabaricones B and C ( 19 and 20 ) and four new compounds 21 – 24 displayed inhibitory activities against sEH, with IC 50 values ranging from 14.24 to 46.35 µM. Additionally, the binding mechanism, key binding interactions, stability, and dynamic behaviour of the active compounds with the sEH enzyme were analysed using in silico molecular docking and dynamics simulations. Our findings suggest that nutmeg could become a promising natural source for discovering and developing new sEH inhibitors.

Neolignans and Diarylnonanoid Derivatives with Anti-inflammatory Activity from Myristica fragrans Houtt. Seeds

“…Collectively, the use of one- and two-dimensional NMR (COSY, HSQC, HMBC, and NOESY) permitted assignments of all the 1 H and 13 C signals for 1 (Table ). In addition, a planar structure of 1 was determined, in an agreement with the planar structure of myrifragranone B reported by Oanh et al However, the determination of the relative configuration of 1 as the threo -form through the NOESY correlation between H-10 and H-12, as described in the aforementioned report, was found to be incorrect because of the spatial proximity of these protons. This was further proven because the NOESY correlation between H-10 and H-12 was also observed in 2 ( erythro -form).…”

“…Myricone A ( 1 ) is also known as myrifragranone B and was obtained as a yellowish gum with a molecular formula of C 42 H 50 O 10 from the ion peak at m / z 737.3302 [M + Na] + in the positive ion HRESIMS (calcd. for C 42 H 50 O 10 Na, 737.3302).…”

“…Subfraction 21-5 was applied again to a Sephadex LH-20 column eluted with MeOH–H 2 O (3:10 → 100% MeOH) to obtain 67 subfractions (21-5-1 to 21-5-67). Myricone E ( 5 , 4.2 mg), myricone F ( 6 , 6.2 mg), giganteone A ( 26 , 3.1 mg), giganteone B ( 28 , 2.3 mg), and giganteone C ( 27 , 2.1 mg) from subfraction 21-5-61, myricone A or myrifragranone B ( 1 , 46.2 mg), myricone B ( 2, 34.8 mg), myricone C ( 3 , 21.6 mg), myricone D ( 4 , 13.3 mg), myricone G ( 7 , 1.3 mg), myrifragranone A ( 8 , 4.3 mg), malabaricone B , ( 23, 19.1 mg), and malabaricone C , ( 24 , 113.3 mg) from subfraction 21-5-63, the mixture of myricone H, I ( 9a and 9b , 11.5 mg), myricone K ( 10 , 5.3 mg), myricone L ( 11 , 6.4 mg), myricone M ( 12 , 5.7 mg), and myricone N ( 13 , 1.4 mg) from subfraction 21-5-65; myricone O ( 14 , 7.5 mg), myricone P ( 15 , 7.3 mg), myricone R ( 16 , 1.2 mg), myricone Q ( 17, 3.1 mg), myricone T ( 18, 3.3 mg), myricone X ( 19, 2.9 mg), myricone Z ( 21, 2.1 mg), and myricone W ( 22, 1.1 mg) from subfraction 21-5-60, myrifratin D ( 38 , 1.6 mg), myrifratin E ( 39 , 1.8 mg), malabaricone A ( 40 , 2.9 mg), myricone J ( 41 , 5.6 mg), myricone S ( 42 , 1.6 mg), and myricone U ( 43 , 2.3 mg) from subfraction 21-5-57, myfracone G ( 50 , 1.7 mg), myfracone H ( 51 , 1.9 mg), and myfracone I ( 52 , 0.7 mg) from subfraction 21-5-58 were purified using preparative MPLC with ACN/H 2 O (isocratic, 70% ACN, flow rate 8 mL/min). Fraction MFMC-28 (550 mg) was separated on a Sephadex LH-20 column eluted with MeOH–H 2 O (3:10 → 100% MeOH), then purified using preparative MPLC with ACN/H 2 O (gradient, flow rate 5 mL/min) to afford trans -3,4-dimethoxycinnamic acid ( 37, 2.5 mg), promalabaricone B ( 25 , 1.9 mg), and myricone Y ( 20 , 2.2 mg).…”

“…The compounds(1−19, 21−22, 41−48, and 50−52) isolated in this study were categorized into six groups (I−VI) based on the manner in which structural part 2 was substituted in structural part 1 and the specific properties of part 2 (seeChart 1,. In this paper, we provide structure determination for one representative compound from each group, and those of the other compounds can be found in the Supporting Information.Myricone A (1) is also known as myrifragranone B19 and was obtained as a yellowish gum with a molecular formula of C 42 H 50 O 10 from the ion peak at m/z 737.3302[M + Na] + in the positive ion HRESIMS (calcd. for C 42 H 50 O 10 Na, 737.3302).…”