Malabaricone B

Naturally Derived Malabaricone B as a Promising Bactericidal Candidate Targeting Multidrug-Resistant Staphylococcus aureus also Possess Synergistic Interactions with Clinical Antibiotics.[Pubmed:37887184]

Antibiotics (Basel). 2023 Sep 26;12(10):1483.

The emergence of multidrug-resistant (MDR) superbugs underlines the urgent need for innovative treatment options to tackle resistant bacterial infections. The clinical efficacy of natural products directed our efforts towards developing new antibacterial leads from naturally abundant known chemical structures. The present study aimed to explore an unusual class of phenylacylphenols (malabaricones) from Myristicamalabarica as antibacterial agents. In vitro antibacterial activity was determined via broth microdilution, cell viability, time-kill kinetics, biofilm eradication, intracellular killing, and checkerboard assays. The efficacy was evaluated in vivo in murine neutropenic thigh and skin infection models. Confocal and SEM analyses were used for mechanistic studies. Among the tested isolates, Malabaricone B (NS-7) demonstrated the best activity against S. aureus with a favorable selectivity index and concentration-dependent, rapid bactericidal killing kinetics. It displayed equal efficacy against MDR clinical isolates of S. aureus and Enterococci, efficiently clearing S. aureus in intracellular and biofilm tests, with no detectable resistance. In addition, NS-7 synergized with daptomycin and gentamicin. In vivo, NS-7 exhibited significant efficacy against S. aureus infection. Mechanistically, NS-7 damaged S. aureus membrane integrity, resulting in the release of extracellular ATP. The results indicated that NS-7 can act as a naturally derived bactericidal drug lead for anti-staphylococcal therapy.

Malabaricones from the fruit of Myristica cinnamomea King as potential agents against Acanthamoeba castellanii.[Pubmed:37783284]

Acta Trop. 2023 Dec;248:107033.

Acanthamoeba castellanii is an opportunistic free-living amoeba (FLA) pathogen which can cause fatal central nervous system (CNS) infection, granulomatous amoebic encephalitis (GAE) and potentially blinding ocular infection, Acanthamoeba keratitis (AK). Acanthamoeba species remain a challenging protist to treat due to the unavailability of safe and effective therapeutic drugs and their ability to protect themselves in the cyst stage. Natural products and their secondary metabolites play a pivotal role in drug discovery against various pathogenic microorganisms. In the present study, the ethyl acetate extract of Myristica cinnamomea King fruit was evaluated against A. castellanii (ATCC 50492), showing an IC(50) of 45.102 +/- 4.62 microg/mL. Previously, the bio-guided fractionation of the extract resulted in the identification of three active compounds, namely Malabaricones (A-C). The isolated and thoroughly characterized acylphenols were evaluated for their anti-amoebic activity against A. castellanii for the first time. Among tested compounds, Malabaricone B (IC(50) of 101.31 +/- 17.41 microM) and Malabaricone C (IC(50) of 49.95 +/- 6.33 microM) showed potent anti-amoebic activity against A. castellanii trophozoites and reduced their viability up-to 75 and 80 %, respectively. Moreover, both extract and Malabaricones also significantly (p < 0.05) inhibit the encystation and excystation of A. castellanii, while showed minimal toxicity against human keratinocyte cells (HaCaT cells) at lower tested concentrations. Following that, the explanation of the possible mechanism of action of purified compounds were assessed by detection of the state of chromatin. Hoechst/PI 33342 double staining showed that necrotic cell death occurred in A. castellanii trophozoites after 8 h treatment of Malabaricones (A-C). These findings demonstrate that Malabaricones B and C could serve as promising therapeutic options against A. castellanii infections.

Evaluation of Antioxidant and Anti-alpha-glucosidase Activities of Various Solvent Extracts and Major Bioactive Components from the Seeds of Myristica fragrans.[Pubmed:33171671]

Molecules. 2020 Nov 8;25(21):5198.

Myristica fragrans is a well-known species for flavoring many food products and for formulation of perfume and medicated balm. It is also used to treat indigestion, stomach ulcers, liver disorders, and, as emmenagogue, diaphoretic, diuretic, nervine, and aphrodisiac. We examined antioxidant properties and bioactive compounds in various solvent extracts from the seeds of M. fragrans. Methanol, ethanol, and acetone extracts exhibited relatively strong antioxidant activities by 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), superoxide radical, and hydroxyl radical scavenging tests. Furthermore, methanol extracts also displayed significant anti-alpha-glucosidase activity. Examined and compared to the various solvent extracts for their chemical compositions using HPLC analysis, we isolated the ten higher content compounds and analyzed antioxidant and anti-alpha-glucosidase activities. Among the isolates, dehydrodiisoeugenol, Malabaricone B and malabaricone C were main antioxidant components in seeds of M. fragrans. Malabaricone C exhibited stronger antioxidant capacities than others based on lower half inhibitory concentration (IC(50)) values in DPPH and ABTS radical scavenging assays, and it also showed significant inhibition of alpha-glucosidase. These results shown that methanol was found to be the most efficient solvent for extracting the active components from the seeds of M. fragrans, and this material is a potential good source of natural antioxidant and alpha-glucosidase inhibitor.

Spice-derived phenolic, malabaricone B induces mitochondrial damage in lung cancer cells via a p53-independent pathway.[Pubmed:30318526]

Food Funct. 2018 Nov 14;9(11):5715-5727.

The spice-derived phenolic, Malabaricone B (mal B) showed selective toxicity to human lung cancer (A549), malignant melanoma (A375) and T cell leukemia (Jurkat) cell lines, without showing toxicity to human normal intestinal (INT407), human kidney (HEK293) and lung fibroblast (WI-38) cells. Among the chosen cancer cell lines, mal B showed maximum cytotoxicity to the A549 cells (IC50 = 8.1 +/- 1.0 muM), which was significantly better than that of curcumin (IC50 = 26.7 +/- 3.1 muM). Further morphological studies by phase contrast microscopy and a clonogenic assay of the A549 cells revealed that mal B treatment increased the number of shrinking cells and also abolished the clonal proliferation of the cells. Mal B induced apoptotic cell death was confirmed by DNA laddering and quantified by cytoplasmic oligonucleosome formation and annexin V/PI assays. The mal B-induced apoptosis was mediated by an increase in the intracellular reactive oxygen species (ROS), because the cell-permeable antioxidants, N-acetylcysteine (NAC) and PEG-SOD, strongly inhibited its cytotoxicity to the A549 cells. Mal B increased the BAX level while simultaneously decreasing the BCL-2 and BCL-XL levels in the A549 cells, triggering the mitochondrial apoptotic pathway as revealed from the release of cytochrome c, and the activation of caspase-9 and caspase-3. Pre-treatment of cells with caspase-9, caspase-3 and pan-caspase inhibitors made them more resistant to mal B treatment. This effect of mal B was strongly associated with the concomitant decrease in anti-apoptotic (IAP1, IAP2 and survivin), angiogenic (growth factors) and cancer invasiveness (matrix metalloproteinase-9, COX-2) modulating proteins. Mal B induced cytotoxicity was unaffected by the shRNA-mediated depletion of p53 in A549 cells. Most importantly, mal B sensitized a wide range of human carcinoma cells regardless of their p53 status. Finally, mal B (100 mg kg-1) also inhibited lung tumor (xenograft) growth in SCID mice.

Antidiabetic potential of phytochemicals isolated from the stem bark of Myristica fatua Houtt. var. magnifica (Bedd.) Sinclair.[Pubmed:29789207]

Bioorg Med Chem. 2018 Jul 23;26(12):3461-3467.

Phytochemical investigation of the stem bark of Myristica fatua Houtt. led to the isolation of a new compound 1 (3-tridecanoylbenzoic acid), along with six known acylphenols (2-7). All the compounds displayed moderate inhibitory activity on alpha-amylase and significant activity on alpha-glucosidase; however Malabaricone B (6) and C (7) were identified as potent alpha-glucosidase inhibitors with IC(50) values of 63.70 +/- 0.546, and 43.61 +/- 0.620 microM respectively. Acylphenols (compounds 3-7) also showed significant antiglycation property. The molecular docking and dynamics simulation studies confirmed the efficient binding of malabaricone C with C-terminus of human maltase-glucoamylase (2QMJ). Malabaricone B also enhanced the 2-NBDG [2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy glucose] uptake in L6 myotubes. These findings demonstrate that acylphenols isolated from Myristica fatua Houtt. can be considered as a lead scaffold for the treatment of type II diabetes mellitus.

HPLC-Guided Isolation, Purification and Characterization of Phenylpropanoid and Phenolic Constituents of Nutmeg Kernel (Myristica fragrans).[Pubmed:27396199]

Nat Prod Commun. 2016 Apr;11(4):483-8.

Many studies on the biological activities of nutmeg continue to appear in the literature. The most common targets include GIT, CNS, oxidative stress and inflammation. However, results obtained from most studies are often inconsistent due to the variability of utilized samples, lack of standardized nutmeg products or insufficient amounts of pure compounds for comprehensive follow-up investigation. To address the consistency and supply issue we utilized available technology to develop a reproducible procedure for preparation of specific extracts and isolation of the major phenolic constituents present in nutmeg kemel. A well-defined and reproducible sequence of extraction, fractionation and chromatographic purification was adopted and was guided by HPLC fingerprinting. Spectroscopic methods, mainly NMR, and mass spectrometry were utilized to identify each compound. Thirteen compounds were isolated in a pure form and identified as: elemicin (1), isoelemicin (2), myristicin (4), surinamensin (5), malabaricone C (6), 2-(3'-allyl-2',6'-dimethoxy-phenyloxy)-l- acetoxy-(3,4-dimethoxyphenyl)-propyl ester (7), methoxylicarin A (8), licarin A (9), Malabaricone B (10), licarin C (11), 5'-methoxylicarin B (12), licarin B (13), and 2-(3'-allyl-2',6'-dimethoxy-phenyloxy)-l-methyl-5-methoxy-1,2-dihydrobenzofuran (3, a new compound). With repeated isolation runs, these pure compounds can be prepared in quantities sufficient for biological evaluation as needed. The availability of purified compounds will also allow the development of specific, accurate, and sensitive analytical procedures for pharmacokinetic studies and for quality control of nutmeg products. Both aspects are essential for nutmeg-focused drug discovery. The same approach can also be adapted to other medicinal plants of potential interest.

Gas-phase reactivity of acylphenols in electrospray and matrix-assisted laser desorption ionization mass spectrometry.[Pubmed:19423907]

Eur J Mass Spectrom (Chichester). 2009;15(2):221-30.

Acylphenols from Myristica crassa were identified based on liquid chromatography high-resolution mass spectrometry and liquid chromatography tandem mass spectrometry (MS/MS) experiments. Two types of compound were found in the extract of the plant: monomeric (Malabaricone B and C) and dimeric compounds (C-C bonded biphenyl and C-C bonded phenyl-linear carbon chain). Evidence of formation of covalent dimeric ions during the electrospray ionization and matrix-assisted laser desorption ionization (MALDI) processes was established. [2M-3H](-) dimeric ions were detected on the mass spectra of each monomeric compound during high-performance liquid chromatography separation. The MS/MS spectra of those species were compared to the MS/MS spectra obtained for the dimeric compounds synthesized by the plant. Fragmentation pathways were studied for the two classes of dimer. The dimeric ions formed in the ion source were C-C bonded biphenyl compounds. Further evidence was obtained from MALDI experiments: increase in the extraction delay time leads to an increase of the dimeric ions relative abundance. Their formation is based on the high reactivity of phenols or phenolate ions which are easily oxidized yielding phenoxy radicals.

Regulation of arginase/nitric oxide synthesis axis via cytokine balance contributes to the healing action of malabaricone B against indomethacin-induced gastric ulceration in mice.[Pubmed:19291837]

Int Immunopharmacol. 2009 Apr;9(4):491-8.

The role of the arginine-metabolism in the healing action of the Myristica malabarica phenol Malabaricone B (mal B) and omeprazole against indomethacin-induced stomach ulceration in mouse was investigated. Indomethacin (18 mg kg- 1) was found to induce maximum stomach ulceration in Swiss albino mice on the 3rd day of its administration, which was associated with reduced arginase activity (30.8%, P < 0.01), eNOS expression, along with increased iNOS expression, total NOS activity (5.55 folds, P < 0.001), NO generation (2.19 folds, P < 0.001), and ratio of pro-/anti-inflammatory cytokines. Besides providing comparable healing as omeprazole (3 mg kg- 1 x 3 days), mal B (10 mg kg- 1 x 3 days, p. o.) shifted the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity (51.6%, P < 0.001), eNOS expression, and reduced iNOS expression, total NOS activity (approximately 75%, P < 0.001), and NO level (50.6%, P < 0.01). These could be attributed to a favourable anti/pro inflammatory cytokines ratio, generated by mal B. The healing by omeprazole was however, not significantly associated with those parameters.

Angiogenic and cell proliferating action of the natural diarylnonanoids, malabaricone B and malabaricone C during healing of indomethacin-induced gastric ulceration.[Pubmed:18071876]

Pharm Res. 2008 Jul;25(7):1601-9.

PURPOSE: To evaluate the plant phenolics, Malabaricone B (mal B) and malabaricone C (mal C) in healing stomach ulcer by modulating angiogenesis. MATERIALS AND METHODS: Male Swiss albino mice, ulcerated with indomethacin (18 mg/kg, p. o., single dose) were treated up to 7 days with different doses of mal B or mal C. The healing capacities of the drugs and their effects on the angiogenic parameters were assessed. RESULTS: Maximum ulceration, observed on the 3rd day after indomethacin administration was effectively healed by mal B and mal C (each 10 mg/kg, p. o. x 3 days), the latter showing equivalent potency (~78% p < 0.001) as that of Omez (3 mg/kg, p. o. x 3 days) and misoprostol (10 mug/kg, p. o. x 3 days). Compared to the untreated mice, those treated with mal B or mal C respectively for 3 days increased the mucosal EGF level (139 and 178%, p < 0.001), the serum VEGF level (56%, p < 0.01 and 95%, p < 0.001) and microvessels formation (37%, p < 0.05 and 62%, p < 0.01), while reducing the serum endostatin level (37%, p < 0.05 and 61%, p < 0.01). The relative healing capacities of mal B and mal C correlated well with their respective abilities to modulate the angiogenic factors. The healing by Omez and misoprostol was not due to improved angiogenesis. CONCLUSIONS: The drugs, mal B and mal C could effectively heal indomethacin-induced stomach ulceration in mice by promoting angiogenesis.

Healing properties of malabaricone B and malabaricone C, against indomethacin-induced gastric ulceration and mechanism of action.[Pubmed:17977527]

Eur J Pharmacol. 2008 Jan 14;578(2-3):300-12.

The healing activity of Malabaricone B and malabaricone C, the major antioxidant constituents of the spice Myristica malabarica against the indomethacin-induced gastric ulceration in mice has been studied. The histological indices revealed maximum ulceration on the 3rd day after indomethacin administration, which was effectively healed by Malabaricone B, malabaricone C (each 10 mg/kg body weight/day) and omeprazole (3 mg/kg body weight/day) for 3 days. Compared to the untreated ulcerated mice, treatment with Malabaricone B, malabaricone C and omeprazole reduced the ulcer indices by 60.3% (P<0.01), 88.4% and 86.1% respectively (P<0.001). All the test samples accelerated ulcer healing than observed in natural recovery even after 7 days. Stomach ulceration reduced the total antioxidant status of plasma by 41% (P<0.05), which was significantly increased by Malabaricone B (36%, P<0.01), malabaricone C (61%, P<0.001) and omeprazole (53%, P<0.001). Compared to the ulcerated untreated mice, those treated with Malabaricone B reduced the levels of thiobarbituric acid reactive substances and protein carbonyls by 17% and approximately 34% respectively (P<0.05), while malabaricone C and omeprazole reduced the parameters almost equally (approximately 30%, P<0.01, and approximately 40%, P<0.01 respectively). Likewise, all the test samples reduced the oxidation of protein and non-protein thiols significantly (P<0.05). The antioxidant activity of the test samples could partly account their healing capacities. However, the differential potency of them was explainable by considering their relative abilities to modulate mucin secretion, PGE(2) synthesis and expression of EGF receptor and COX isoforms, malabaricone C being most effective in controlling all these factors.

Isolation and characterization of two antimicrobial agents from mace (Myristica fragrans).[Pubmed:1955885]

J Nat Prod. 1991 May-Jun;54(3):856-9.

The two antimicrobial resorcinols Malabaricone B [1] and malabaricone C [2] were isolated from mace, the dried seed covers of Myristica fragrans. Both compounds exhibited strong antifungal and antibacterial activities. Structure modifications by methylation or reduction resulted in diminished activity.