Phaleria macrocarpa (Scheff.) Boerl. is geographically distributed around Papua Island, Indonesia. Traditionally, P. macrocarpa is exercised to reduce pain, stomachache, diarrhea, tumor problems, blood glucose, cholesterol, and blood pressure. A growing interest in the medicinal values of P. macrocarpa especially in Asia reflects the usage of diverse extraction techniques, particularly modern approaches. In this review article, the extraction methods and solvents relevant to P. macrocarpa were discussed, with the extent of its pharmacological activities. Recent bibliographic databases such as Google Scholar, PubMed, and Elsevier between 2010 and 2022 were assessed. Based on the findings, the pharmacological studies of P. macrocarpa are still pertinent to its traditional uses but primarily emphasise anti-proliferative activity especially colon and breast cancer cells with low toxicity and fruit as the most studied plant part. The utilization of modern separation techniques has predominantly been aimed at extracting mangiferin and phenolic-rich compounds and evaluating their antioxidant capacity. However, the isolation of bioactive compounds remains a challenge, leading to the extensive utilization of the extracts in in vivo studies. This review endeavors to highlight modern extraction methods that could potentially be used as a point of reference in the future for exploring novel bioactive compounds and drug discovery on a multi-scale extraction level.

Alzheimer’s disease (AD) causes progressive memory loss and cognitive dysfunction. It is triggered by multifaceted burdens such as cholinergic toxicity, insulin resistance, neuroinflammation, and oxidative stress. Syzygium plants are ethnomedicinally used in treating inflammation, diabetes, as well as memory impairment. They are rich in antioxidant phenolic compounds, which can be multi-target neuroprotective agents against AD. This review attempts to review the pharmacological importance of the Syzygium genus in neuroprotection, focusing on anti-cholinesterase, anti-diabetic, anti-inflammatory, and antioxidant properties. Articles published in bibliographic databases within recent years relevant to neuroprotection were reviewed. About 10 species were examined for their anti-cholinesterase capacity. Most studies were conducted in the form of extracts rather than compounds. Syzygium aromaticum (particularly its essential oil and eugenol component) represents the most studied species owing to its economic significance in food and therapy. The molecular mechanisms of Syzygium species in neuroprotection include the inhibition of AChE to correct cholinergic transmission, suppression of pro-inflammatory mediators, oxidative stress markers, RIS production, enhancement of antioxidant enzymes, the restoration of brain ions homeostasis, the inhibition of microglial invasion, the modulation of ß-cell insulin release, the enhancement of lipid accumulation, glucose uptake, and adiponectin secretion via the activation of the insulin signaling pathway. Additional efforts are warranted to explore less studied species, including the Australian and Western Syzygium species. The effectiveness of the Syzygium genus in neuroprotective responses is markedly established, but further compound isolation, in silico, and clinical studies are demanded.

Acetylcholinesterase (AChE) inhibitors remain the primary therapeutic drug that can alleviate Alzheimer’s disease’s (AD) symptoms. Several Cassia species have been shown to exert significant anti-AChE activity, which can be an alternative remedy for AD. Cassia timoriensis and Cassia grandis are potential plants with anti-AChE activity, but their phytochemical investigation is yet to be further conducted. The aims of this study were to identify the phytoconstituents of C. timoriensis and C. grandis and evaluate their inhibitory activity against AChE and butyrylcholinesterase (BChE). Two compounds were isolated for the first time from C. timoriensis: arachidyl arachidate (1) and luteolin (2). Five compounds were identified from C. grandis: β-sitosterol (3), stigmasterol (4), cinnamic acid (5), 4-hydroxycinnamic acid (6), and hydroxymethylfurfural (7). Compound 2 showed significant inhibition towards AChE (IC₅₀: 20.47 ± 1.10 µM) and BChE (IC₅₀: 46.15 ± 2.20 µM), followed by 5 (IC_50: 40.5 ± 1.28 and 373.1 ± 16.4 µM) and 6 (IC₅₀: 43.4 ± 0.61 and 409.17 ± 14.80 µM) against AChE and BChE, respectively. The other compounds exhibited poor to slightly moderate AChE inhibitory activity. Molecular docking revealed that 2 showed good binding affinity towards TcAChE (PDB ID: 1W6R) and HsBChE (PDB ID: 4BDS). It formed a hydrogen bond with TYR121 at the peripheral anionic site (PAS, 2.04 Å), along with hydrophobic interactions with the anionic site and PAS (TRP84 and TYR121, respectively). Additionally, 2 formed three H-bonds with the binding site residues: one bond with catalytic triad, HIS438 at distance 2.05 Å, and the other two H-bonds with GLY115 and GLU197 at distances of 2.74 Å and 2.19 Å, respectively. The evidence of molecular interactions of 2 may justify the relevance of C. timoriensis as a cholinesterase inhibitor, having more promising activity than C. grandis.

Seventeen methanol extracts from different plant parts of five different Cassia species, including C. timorensis, C. grandis, C. fistula, C. spectabilis, and C. alata were screened against acetylcholinesterase (AChE). C. timorensis extracts were found to exhibit the highest inhibition towards AChE whereby the leaf, stem, and flower methanol extracts showed 94–97% inhibition. As far as we are aware, C. timorensis is one of the least explored Cassia spp. for bioactivity. Further fractionation led to the identification of six compounds, isolated for the first time from C. timorensis: 3-methoxyquercetin (1), benzenepropanoic acid (2), 9,12,15-octadecatrienoic acid (3), β-sitosterol (4), stigmasterol (5), and 1-octadecanol (6). Compound 1 showed moderate inhibition towards AChE (IC₅₀: 83.71 μM), while the other compounds exhibited poor to slightly moderate AChE inhibitory activity. Molecular docking revealed that the methoxy substitution of 1 formed a hydrogen bond with TYR121 at the peripheral anionic site (PAS) and the hydroxyl group at C5 formed a covalent hydrogen bond with ASP72. Additionally, the OH group at the C3′ position formed an interaction with the protein at the acyl pocket (PHE288). This possibly explains the activity of 1 in blocking the entry of acetylcholine (ACh, the neurotransmitter), thus impeding the hydrolysis of ACh.

Despite much interest and studies toward the genus Podocarpus, the anti-malarial evaluation of Podocarpus polystachyus’s phytoconstituents remains lacking. Herein, the phytoconstituents of P. polystachyus leaves and their anti-malarial effect against Plasmodium falciparum were investigated for the first time. One new natural product, 8ß,13ß-kaur-15-en-17-al (1), along with three known compounds, 8ß,13ß-kaur-15-en-17-ol (2) and 13ß-kaur-16-ene (3), and α-tocopherol hydroquinone (4) were isolated via HR-ESI-MS and NMR analyses. Compounds 1 and 2 inhibited P. falciparum growth at 12 and 52 µM of IC₅₀, respectively. Their anti-malarial activity was associated with the in silico P. falciparum lactate dehydrogenase (PfLDH) inhibition. Molecular docking of ligands 1 and 2 with the putative target PfLDH revealed ~−2 kcal/mol of binding energies more negative than the control. Molecular dynamic simulations (100 ns) showed equal or smaller deviation values (RMSD, RMSF, Rg) and stronger interactions of PfLDH-1 and PfLDH-2 complexes via at least one consistent H-bond than the control. Additionally, a slightly increased PfLDH H-bond profile in their interactions improved the PfLDH dynamic and structural stabilities. Overall, this study supports the relevance of 1 and 2 as plasmodial growth inhibitors with their putative anti-PfLDH activity, which could be a potential scaffold for developing anti-malarial drugs.

A new peptaibol, RK-026A (1) was isolated from a fungus, Trichoderma sp. RK10-F026, along with atroviridin B (2), alamethicin II (3), and polysporin B (4) as a cytotoxic compound, which was selected by principal component analysis of the MS data from 5 different culture conditions. The structure of 1 was determined as a new atroviridin B derivative containing Glu at the 18th residue instead of Gln by NMR and HR-MS analyses including the investigation of detailed MS/MS fragmentations. 1 showed cytotoxicity toward K562 leukemia cells at an IC₅₀ value of 4.1 µm.