Discovering future cures from phytochemistry to metabolomics

Eukaryotes such as higher plants have evolved to produce a diverse range of low-molecular-weight compounds known as secondary metabolites or phytochemicals, that can be used as food and feed additives, flavours, fragrances, cosmetics, agrochemicals and pharmaceuticals. The chemical diversity of plants is more complex than any chemical library made by humans, and the plant kingdom therefore represents an enormous reservoir of valuable molecules just waiting to be discovered. There are approximately 298,000 species of higher plants, less than 10% of which have been chemically characterized to any extent. The majority of plant species are found in tropical rain forests. Extracts and infusions containing natural products from plants have historically been a major source of pharmaceutical ingredients, often comprising mixtures of several bioactive compounds with complex synergistic effects. The first secondary metabolite isolated from plants was morphine (over 200 years ago) and many other natural compounds have since become important pharmaceuticals in modern society. It is often difficult to find synthetic substitutes with the same efficacy and specificity as natural compounds. Consequently, molecules derived from plants make up a sizeable proportion of current high-value drugs, and also provide many new lead compounds for industrial applications. Many companies are undergoing a renaissance in their interest in plant-derived compounds, especially the pharmaceutical industry looking for new drugs, and the cosmetics industry which uses plant extracts, oils and even plant cell cultures in some products. The high structural diversity and complexity of secondary metabolites still pose technical challenges for a phytochemist since the chemical characteristics of the plant compounds vary to a very high degree, for example in the degree of polarity and solubility. Typically such compounds accumulate at low levels in plant tissues and production is strongly correlated to specific vegetative stages. Thus the process of finding, extracting, isolating and purifying these phytochemicals is time-consuming and can be a daunting and challenging task. Further many plants that produce high-value secondary metabolites are difficult to cultivate or are endangered because of over-harvesting and deforestation activities. However, the last decade has seen tremendous development in technology and the birth of new, innovative methods that are now accessible for use by the current generation of researchers. In some cases, what was impossible to do then has become almost routine now. Armed with these new advantages and strength, the continuous exploration of plant biodiversity, using novel and innovative bioassays to evaluate natural compounds for their beneficial effects, is therefore of great scientific, medical and bioeconomic importance. In this inaugural lecture, some highlights of my journey and discoveries made, together with my colleagues and students that I have worked with over the last 15 years of natural products research, will be presented. Our research endeavours which began with a mainly reductionist perpective, in accordance with the then popular drug discovery approaches used by big pharmas and academic laboratories all over the world, has now mellowed into a more holistic approach, utilizing ‘omics’ technologies. Sample size and loss of biological activity due to the reductionist approach of disturbing the inherent synergism of a plant metabolome, has always been a delimiting factor in phytochemistry studies. We believe that systems biology, in particular metabolomics/metabonomics, holds greater promise in our efforts to gain a deeper understanding of a plant metabolome’s effects on a disease state or on other biological perturbations

Chemical constituents of the bark of ryparosa kunstleri (Flacourtiaceae)

The bark of Ryparosa kunstleri yielded the triterpenes friedelin, trichadenic acid B, and the new 3B-p-coumaroyl trichadenic acid as its major constituents. Stictic acid, a depsidone, was also isolated but was deduced to be a contaminant

IN SILICO STUDIES ON DIACYL DERIVATIVES OF PHLOROGLUCINOL TO ENHANCE PHARMACODYNAMIC AND PHARMACOKINETIC PROFILES OF 2,4,6-TRIHYDROXY-3-GERANYL-ACETOPHENONE

Objective: The purpose of this study was to evaluate the LOX inhibitory activity, and predict the drug likeness properties of designed diacyl derivatives of phloroglucinol, using in silico method. Methods: The designed derivatives were subjected to molecular docking using AUTODOCK while the receptor used in this study was built from SWISS MODEL. Drug likeness properties of the derivatives were calculated by online programs i.e. MOLINSPIRATION and PreADMET. Results: Molecular docking study revealed that designed tHGA derivative with four-carbon chain length exhibited the best binding affinity with the docking scores of -7.26kcal/mol. Three types of binding interactions were observed between the derivatives and the receptor site i.e H-bonding, hydrophobic and Van der Waals interactions. The important amino acid residues involved in H-bonding were Gln495 and Gln697, while other amino acid residues, such as Leu754 and Ile 553, were involved in the Van der Waals interaction. The designed tHGA derivatives were mainly stabilized through hydrophobic interactions with His499, His504, Ile538, Phe557 and Val750. In silico physicochemical calculations predicted that all the designed derivatives passed the Lipinski’s Rule of 5, and have good human intestinal absorption property (HIA>70%). Further, all the designed derivatives showed moderate central nervous system absorption (0.6<BBB<2.0), except for the derivative with a longer (5-Cs) chain length. Conclusion: The findings of the present study suggested that changing the acyl and geranyl side chains of the natural product molecule, tHGA, into two acyl bearing side chains, will improve its pharmacodynamic and pharmacokinetic profiles

Postharvest characteristics of two flowering stages of torch ginger (Etlingera elatior) inflorescences

Torch ginger (Etlingera elatior), a flourish in tropical and subtropical climates crop, with extravagant and showy inflorescence may be used as cut flower at each developmental stage. Limited studies have been undertaken to reveal the postharvest performance of this leafless inflorescence, especially at advanced developmental stages. Therefore, the objective of this study was to elucidate the postharvest performance of the torch ginger inflorescence treated with different vase solutions. Inflorescences at two flowering stages i.e., tight bud stage and torch shows stage at about 35 and 58 days, respectively, after emergence from rhizome, were used in this study. Sucrose (20 g L-1), 8-hydroxyquinoline sulfate (8-HQS, 0.1 g L-1) and distilled water were used as vase solution treatment. Postharvest characteristics, including vase life, relative fresh weight (RFW), dry weight, solution uptake rate, respiration and ethylene production rate were evaluated. Results showed that vase life of tight bud stage inflorescence was significantly higher than torch shows stage irrespective of treatments used. In contrast, significantly higher solution uptake rate was shown in the torch shows stage inflorescence. There was no significant difference in dry weight and respiration rate measured. No ethylene was detected in all treated inflorescences throughout the study. Prolongation of vase life was associated with the increase in RFW. Increase of RFW was found in tight bud stage inflorescence but reduction of RFW was shown in torch stage inflorescence at the end of vase life. The decrease of RFW could be due to the breakdown of stored carbohydrates in peduncle for the development of true flowers for pollination purpose. Supplementation of sucrose promoted the opening of true flowers. The use of 8-HQS and distilled water enabled the development of true flowers, but they failed to open. Sucrose treated inflorescences both in tight bud and torch stage showed better postharvest quality compared to 8-HQS and distilled water

Chemical characterization and antioxidant activity of three medicinal Apiaceae species

Centella asiatica (‘Pegaga’ = Malaysia) is well known plant that has been used as one of the ingredients in pharmaceutical and cosmetic industries. Using liquid chromatography with diode array and electrospray ionization/mass spectrometry (LC–DAD–ESI/MS) analysis, chemical profiling of three different Pegaga extracts (C. asiatica, H. bonariensis and H. sibthorpioides) revealed variations in their metabolite profile. Our findings showed that triterpenes of C. asiatica were characterized by the ursane-type triterpenes (madecassoside, asiaticoside, madecassic acid, and asiatic acid), while the two Hydrocotyle species consisted of oleanane-type triterpenes (barrigenol derivatives). Other variations are due to the difference in phenolic and flavonoid constituents. The three Pegaga extracts were also evaluated for their total phenolic content (TPC), 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, and xanthine oxidase inhibition (XOI) activities. The results showed that C. asiatica has the most potent antioxidant activity (TPC = 72.09 mg/100 g DW; DPPH = 72.99 μg/ml; XOI = 87.68 μg/ml) as compared to H. bonariensis (TPC = 28.55 mg/100 g DW; DPPH = 22.43 μg/ml; XOI = 32.23 μg/ml) and H. sibthorpioides (TPC = 56.23 mg/100 g DW; DPPH = 37.86 μg/ml; XOI = 14.73. μg/ml)

Comparison of Partial Least Squares and Artificial Neural Network for the prediction of antioxidant activity in extract of pegaga (centella) varieties from 1H Nuclear Magnetic Resonance spectroscopy.

Multivariate data analysis of 1H Nuclear Magnetic Resonance spectra was applied for the prediction of antioxidant activity in five different Pegaga (C. asiatica (var 1), C. asiatica (var 2), C. asiatica (var 3) H. bonariensis and H. sibthorpioides) varieties. Linear (Partial Least Square regression) and non linear (Artificial Neural Network) models have been developed and their performances were compared. The performances of the models were tested according to external validation of prediction set. The result showed that the Partial Least Square model provided better generalization than Artificial Neural Network. Despite those, both models are considered reasonably acceptable. Regression coefficient and VIP values of the PLS model revealed that 3,5-O-dicaffeoyl-4-O-malonilquinic acid (irbic acid), 3,5-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, 5-O-caffeoylquinic acid (chlorogenic acid), quercetin and kaempferol derivatives are the components responsible for the antioxidant activity. In addition, the spectroscopic pattern of the Pegaga varieties, as shown by the PLS score plots was consistent with the corresponding antioxidant activity. Prediction of the antioxidant activity from 1H NMR spectra using this approach is useful in assessing the quality of medicinal herb extracts

Phenological growth stages of torch ginger (Etlingera elatior) inflorescence

Torch ginger (Etlingera elatior) inflorescence with its showy appearance can be used as a cut flower. However, the development of inflorescence has not been studied. The aim of this study is to determine the phenological stages of torch ginger inflorescence from the emergence of rhizome until full bloom stage using the extended BBCH scale. The growth stages of the inflorescence are categorised into peduncle elongation, inflorescence emergence, flowering and senescence. It takes about 60 days for the inflorescence to emerge from rhizome and develop to reach full-bloom stage with true flower opening. This study provides important information in understanding this crop

Antioxidant and antiacetylcholinesterase activities of Pluchea indica Less

This study was undertaken to evaluate the antioxidant and acetylcholinesterase inhibition properties of stems and leaf of hexane and methanolic extracts of Pluchea indica. Methanolic extract of leaves showed the highest antioxidant activity (IC50= 24.45 ± 0.34 μg/ml) and total phenolic contents (573.52 ± 6.2 mg GAE/100 g crude extract), in DPPH radical scavenging and Folin-Ciocalteu assays respectively, however, it failed to inhibit acetylcholinesterase in TLC bioautographic detection. The rest of plant extracts, included methanolic extract of stems, hexane extract of both leaves and stems, were detected to have acetylcholinesterase inhibitory properties. Hexane extract of both leaves and stems exhibited lower or negligible level of antioxidant activity and phenolic contents. Pluchea indica may provide a potential natural source of bioactive compounds, and maybe beneficial to the human health

2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase

In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6 μM and 0.6 μM, respectively. Further structure–activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes’ inhibition. The Lineweaver–Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer

Evaluation of the α-glucosidase inhibitory and free radical scavenging activities of selected traditional medicine plant species used in treating diabetes

Plants constitute a major ingredient in traditional or folk medicine. The therapeutic claims made on the use of these traditional medicinal plants range from simple conditions such as fevers and migraines, to more complex diseases such as cancer, metabolic syndrome and diabetes mellitus. The aqueous ethanolic extracts of five medicinal plant species; Cosmos caudatus, Leucaena leucocephala, Momordica charantia, Pereskia bleo and Averrhoa bilimbi were assessed for glucose lowering effect via the in vitro α-glucosidase inhibition assay. Their antioxidant potential, represented by their DPPH radical scavenging activity and total phenolic contents were also measured. The most potent α-glucosidase inhibitory activity was recorded for the leaf extract of C. caudatus with IC50 of 21.90 ± 3.60 µg/mL, followed by L. leucocephala with IC50 value of 30.80 ± 2.50 µg/mL. Momordica charantia, P. bleo and A. bilimbi did not show any significant inhibition of α-glucosidase. Meanwhile C. caudatus also gave the highest DPPH radical scavenging activity with IC50 value of 272.46 ± 8.98 µg/mL, and the highest total phenolic content with a value of 0.263 ± 0.02 g GAE/g DW. The present work provides a priority list of interesting plants for further study with respect to the treatment of diabetes