Potent and Selective Inhibitors of Human Monoamine Oxidase A from an Endogenous Lichen Fungus Diaporthe mahothocarpus

Abstract

Using 126 endogenous lichen fungus (ELF) extracts, inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) were evaluated. Among them, extract ELF29 of the endogenous fungus Diaporthe mahothocarpus of the lichen Cladonia symphycarpia showed the highest inhibitory activity against hMAO-A. Compounds alternariol (AT), 5′-hydroxy-alternariol (HAT), and mycoepoxydiene (MED), isolated from the extract, had potent inhibitory activities against hMAO-A with IC50 values of 0.020, 0.31, and 8.68 µM, respectively. AT, HAT, and MED are reversible competitive inhibitors of hMAO-A with Ki values of 0.0075, 0.116, and 3.76 µM, respectively. The molecular docking studies suggested that AT, HAT, and MED had higher binding affinities for hMAO-A (−9.1, −6.9, and −5.6 kcal/mol, respectively) than for hMAO-B (−6.3, −5.2, and −3.7 kcal/mol, respectively). The relative tight binding might result from a hydrogen bond interaction of the three compounds with a Tyr444 residue in hMAO-A, whereas no hydrogen bond interaction was proposed in hMAO-B. In silico pharmacokinetics, the three compounds showed high gastrointestinal absorption without violating Lipinski’s five rules, but only MED showed high probability to cross the blood–brain barrier. These results suggest that AT, HAT, and MED are candidates for treating neuropsychiatric disorders, such as depression and cardiovascular disease.

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

“…The polyketides alternariol 159, 5′-hydroxyalternariol 160, and mycoepoxydiene 161 were isolated following a bioassay guided paradigm and were found to be MAO-A inhibitors. Compound 159 exhibited the best value with an IC50 of 0.020 μM, while 160 and 161 exhibited IC50 values of 0.31 and 8.7 μM for human MAO-A, respectively [198]. The in vitro evaluation of several endogenous endocannabinoids found that virodhamine 162 inhibited both MAO-A and -B, being preferential to MAO-B with IC50 values of 38.70 and 0.71 μM for human MAO-A and MAO-B, respectively [199].…”

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

“…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.…”

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

“…To evaluate the inhibitory activity of MAO-A, a library of 195 ethyl acetate or butanol extracts from Ukraine-derived lichen endogenous fungi was obtained from Sunchon University Korea Lichen Research Institute (KOLRI). The extract was dissolved in DMSO at a concentration of 10 mg/mL, and the concentration of DMSO in the assay mixture was 0.2% [27]. All other chemicals not specified were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

“…The anthraquinone solorinic acid isolated from the lichen Solorina crocea exhibits MAO inhibitory activity (IC 50 = 14.3 µM) [55], and 4-acylresorcinol, a synthetic derivative of a lichen compound, exhibits MAO inhibitory activity (IC 50 = 4.27 µM) [56]. Alternariol, 5-hydroxy-alternariol, and mycoepoxydiene isolated from ELF Diaporthe mahothocarpus have selective inhibitory activity on hMAO-A [27], and 5-hydroxy-2-methyl-chroman-4-one isolated from ELF Daldinia fissa selectively inhibits hMAO-B [25].…”