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Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.

Nowadays, non-resolving inflammation is becoming a major trigger in various diseases as it plays a significant role in the pathogenesis of atherosclerosis, asthma, cancer, obesity, inflammatory bowel disease, chronic obstructive pulmonary disease, neurodegenerative disease, multiple sclerosis, and rheumatoid arthritis. However, prolonged use of anti-inflammatory drugs is usually accompanied with undesirable effects and hence more patients tend to seek for natural compounds as alternative medicine. Considering the fact above, there is an urgency to discover and develop potential novel, safe and efficacious natural compounds as drug candidates for future anti-inflammatory therapy. Genistein belongs to the flavonoid family, in the subgroup of isoflavones. It is a phytoestrogen that is mainly derived from legumes. It is a naturally occurring chemical constituent with a similar chemical structure to mammalian estrogens. It is claimed to exert many beneficial effects on health, such as protection against osteoporosis, reduction in the risk of cardiovascular disease, alleviation of postmenopausal symptoms and anticancer properties. In the past, numerous in vitro and in vivo studies have been conducted to investigate the anti-inflammatory potential of genistein. Henceforth, this review aims to summarize the anti-inflammatory properties of genistein linking with the signaling pathways and mediators that are involved in the inflammatory response as well as its toxicity profile. The current outcomes are analysed to highlight the prospect as a lead compound for drug discovery. Data was collected using PubMed, ScienceDirect, SpringerLink and Scopus databases. Results showed that genistein possessed strong anti-inflammatory activities through inhibition of various signaling pathways such as nuclear factor kappa-B (NF-κB), prostaglandins (PGs), inducible nitric oxide synthase (iNOS), proinflammatory cytokines and reactive oxygen species (ROS). A comprehensive assessment of the mechanism of action in anti-inflammatory effects of genistein is included. However, evidence for the pharmacological effects is still lacking. Further studies using various animal models to assess pharmacological effects such as toxicity, pharmacokinetics, pharmacodynamics, and bioavailability studies are required before clinical studies can be conducted. This review will highlight the potential use of genistein as a lead compound for future drug development as an anti-inflammatory agent.

In this study, a set of 234 chemical constituents reported from Goniothalamus species were docked against envelope (E), NS2B/NS3, NS5 methyltransferase, and NS5 RdRp dengue virus (DENV) protein. As the result, compounds 95, 96, 97, 100, 149, 155, and 187 were identified as potential dengue protease inhibitors based on minimal docking energy values and multiple interactions with binding sites. The results from in-silico Lipinski’ rule and ADMET analysis showed that compound 149 was predicted as the most potential compound that fulfills the drug-likeness properties. Ligand 149 was found to be able to fit in well and remain stable in the binding site of proteins envelope, NS2B/NS3, NS5 methyltransferase and NS5 RdRp. The results from molecular dynamic simulations indicate that the ligand-protein complex of 149 in NS5 methyltransferase showed the most preferable, successfully interacted within the active sites and were able to reach convergence within 100 ns.

Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) can be inferred from the overexpression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) proteins and the activation of the TLR4/MyD88 cascading signalling pathway. Finding a new inhibitor that can attenuate the activation of this pathway is a novel strategy for reducing PTX chemoresistance. In this study, a series of small molecule compounds were synthesised and tested in combination with PTX against TNBC cells. The trimethoxy-substituted compound significantly decreased MyD88 overexpression and improved PTX activity in MDA-MB-231TLR4+ cells but not in HCCTLR4- cells. On the contrary, the trifluoromethyl-substituted compound with PTX synergistically improved the growth inhibition in both TNBC subtypes. The fluorescence titrations indicated that both compounds could bind with MD2 with good and comparable binding affinities. This was further supported by docking analysis, in which both compounds fit perfectly well and form some critical binding interactions with MD2, an essential lipid-binding accessory to TLR4 involved in activating the TLR-4/MyD88-dependent pathway.

In this Minireview, we discuss some of the important palladium‐catalysed cross‐coupling reactions utilised in the synthesis of the enone system of chalcones. Examples given here not only exemplify the efficiency and practicality of new C−C bond formation of the enone system via palladium‐catalysed reactions but also reflect some of the revolutionary methods used for the preparation of a more complex and valuable chalcone scaffold which is known to be a privileged structure in the field of medicinal chemistry.

Phyllanthus amarus Schum. &amp, Thonn. (Phyllanthaceae) is a medicinal plant that is commonly used to treat diseases such as asthma, diabetes, and anemia. This study aimed to examine the antiallergic activity of P. amarus extract and its compounds. The antiallergic activity was determined by measuring the concentration of allergy markers release from rat basophilic leukemia (RBL-2H3) cells with ketotifen fumarate as the positive control. As a result, P. amarus did not stabilize mast cell degranulation but exhibited antihistamine activity. The antihistamine activity was evaluated by conducting a competition radioligand binding assay on the histamine 1 receptor (H1R). Four compounds were identified from the high performance liquid chromatography (HPLC) analysis which were phyllanthin (1), hypophyllanthin (2), niranthin (3), and corilagin (4). To gain insights into the binding interactions of the most active compound hypophyllanthin (2), molecular docking was conducted and found that hypophyllanthin (2) exhibited favorable binding in the H1R binding site. In conclusion, P. amarus and hypophyllanthin (2) could potentially exhibit antiallergic activity by preventing the activation of the H1 receptor.

A new series of pyrazole, phenylpyrazole, and pyrazoline analogs of diarylpentanoids (excluding compounds 3a, 4a, 5a, and 5b) was pan-assay interference compounds-filtered and synthesized via the reaction of diarylpentanoids with hydrazine monohydrate and phenylhydrazine. Each analog was evaluated for its anti-inflammatory ability via the suppression of nitric oxide (NO) on IFN-γ/LPS-activated RAW264.7 macrophage cells. The compounds were also investigated for their inhibitory capability toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), using a modification of Ellman's spectrophotometric method. The most potent NO inhibitor was found to be phenylpyrazole analog 4c, followed by 4e, when compared with curcumin. In contrast, pyrazole 3a and pyrazoline 5a were found to be the most selective and effective BChE inhibitors over AChE. The data collected from the single-crystal X-ray diffraction analysis of compound 5a were then applied in a docking simulation to determine the potential binding interactions that were responsible for the anti-BChE activity. The results obtained signify the potential of these pyrazole and pyrazoline scaffolds to be developed as therapeutic agents against inflammatory conditions and Alzheimer's disease.

Inhibition of xanthine oxidase (XO) activity is an effective therapeutic approach for the treatment of diseases such as gout and hyperuricemia. Additionally, the use of XO inhibitors can further be extended to injury treatments such as ischemic reperfusion in various organs such as heart, liver and kidney. In this study, 7 aurone compounds were synthesized and tested on XO and compared with the positive control allopurinol. Compound 5e was identified as the most potent compound and was able to inhibit half of XO activity at 33.23 μM followed by compounds 5f and 5d at 210.22 μM and 302.0 μM, respectively. Finally, molecular docking study was conducted to understand the important binding interactions of the selected aurone with the active site of XO. DOI : http://dx.doi.org./10.17576/JSKM-2018-1601-17