(S)-5-Methylmellein Isolated from an Endogenous Lichen Fungus Rosellinia corticium as a Potent Inhibitor of Human Monoamine Oxidase A

Abstract

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 µM for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 µM). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 µM) but very weakly inhibited butyrylcholinesterase and β-secretase. Compound 5MM had a Ki value of 2.45 μM and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (−6.8 kcal/mol) than hMAO-B (−6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (−6.6 kcal/mol) and hMAO-B (−5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 Å), while the R-form interacted with the Asn181 residue (2.375 Å). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski’s five rules and showed high gastrointestinal absorption and blood–brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

Natural Products Inhibitors of Monoamine Oxidases—Potential New Drug Leads for Neuroprotection, Neurological Disorders, and Neuroblastoma

“…Another small polyketide, (S)-5-methymellein 156, a small lactone isolated from the endogenous fungus Rosellinia corticium within the lichen Pseudevernia furfuracea, exhibited MAO inhibition. Compound 156 was identified through bioassay guided fractionation and exhibited IC50 values of 5.31 and 9.15 μM for human MAO-A and MAO-B, respectively [196]. Its enantiomer, (R)-5-methylmellein 157, was also isolated from the fermented mycelia of Xylaria nigripes, and 157 showed moderate selectivity toward MAO-A with IC50 values of 4.6 and 38.5 μM for human MAO-A and MAO-B, respectively [197].…”

“…Figure 15 shows the structures and Table 7 presents the IC50 values of selected miscellaneous natural product classes on natural product inhibitors. 196] Note: natural products tested on total MAO are not listed. Enzyme source: F = recombinant human MAO-A and -B.…”

3-Phenethyl-2-phenylquinazolin-4(3H)-one isolated from marine-derived Acremonium sp. CNQ-049 as a dual- functional inhibitor of monoamine oxidases-B and butyrylcholinesterase

“…5B). In previous studies, most of MAO inhibitors were reported as competitive inhibitors [27][28][29][30]32,33], and ChE inhibitors were reported as mixed-type inhibitors [22][23][24]. These results suggested that compound 1 was a competitive MAO-B inhibitor and a mixed-type BChE inhibitor.…”

“…However, compound 1 showed weak inhibitory activity against BACE1 as well as MAO-A and AChE. Compared with other natural inhibitors, MAO-B inhibitory activity of compound 1 was similar or higher than 5MM (IC 50 =9.15 μM) [29], alternariol (AT, IC 50 =20.7 μM) [28], glycyrol (GC, IC 50 =29.48 μM) [40] and chromenone derivative 1 (IC 50 =27.0 μM) [30], but lower than chromenone derivative 2 (IC 50 =3.42 μM) [30], and liquiritigenin (IC 50 =0.098 μM) [40]. In addition, BChE inhibitory activity of compound 1 was slightly lower than GC (IC 50 =7.22 μM) [40].…”

“…Recently, dual-target inhibitors have been developed to increase the efficacy of AD treatment [21], including homoisoflavonoid derivatives [22], donepezil-butylated hydroxytoluene hybrids [23], coumarin-dithiocarbamate hybrids [24], alcohol-bearing dual inhibitors [25], and chalcone oxime ethers [26]. Natural MAO and ChE inhibitors from microbial sources have been isolated and investigated such as 5-hydroxy-2-methyl-chroman-4-one (HMC) from an endogenous lichen fungus (ELF) Daldinia fissa [27], alternariol, 5'-hydroxy-alternariol, and mycoepoxydiene from an ELF Diaporthe mahothocarpus [28], (S)-5-methylmellein (5MM) from an ELF Rosellinia corticium [29], chromenone derivatives from Streptomyces sp. [30], aplysinopsins from Aplysinopsis sp.…”