Bioassay-guided extraction of the stem bark of Knema laurina showed the acetylcholinesterase (AChE) inhibitory activity of DCM and hexane fractions. Further repeated column chromatography of hexane and DCM fractions resulted in the isolation and purification of five alkenyl phenol and salicylic acid derivatives. New compounds, (+)-2-hydroxy-6-(10'-hydroxypentadec-8'(E)-enyl)benzoic acid (1) and 3-pentadec-10'(Z)-enylphenol (2), along with known 3-heptadec-10'(Z)-enylphenol (3), 2-hydroxy-6-(pentadec-10'(Z)-enyl)benzoic acid (4), and 2-hydroxy-6-(10'(Z)-heptadecenyl)benzoic acid (5) were isolated from the stem bark of this plant. Compounds (1-5) were tested for their acetylcholinesterase inhibitory activity. The structures of these compounds were elucidated by the 1D and 2D NMR spectroscopy, mass spectrometry and chemical derivatizations. Compound 5 showed strong acetylcholinesterase inhibitory activity with IC(50) of 0.573 ± 0.0260 μM. Docking studies of compound 5 indicated that the phenolic compound with an elongated side chain could possibly penetrate deep into the active site of the enzyme and arrange itself through π-π interaction, H-bonding, and hydrophobic contacts with some critical residues along the complex geometry of the active gorge.

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.

Curcumin is a highly pleiotropic molecule with significant regulatory effects upon inflammation and inflammatory related diseases. However curcumin has one major important limitation in which it has poor bioavailability. Design of synthetic structural derivatives of curcumin is but one approach that has been used to overcome its poor bioavailability while retaining, or further enhancing, its drug-like effects. We have synthesized a series of curcumin analogues and describe the effects of 2,6-bis-4-(hydroxyl-3-methoxy-benzylidine)-cyclohexanone or BHMC upon nitric oxide and cytokine synthesis in cellular models of inflammation. BHMC showed a significant dose-response inhibitory action upon the synthesis of NO and we have shown that this effect was due to suppression of both iNOS gene and enzyme expression without any effects upon scavenging of nitrite. We also demonstrated that BHMC has a very minimal effect upon iNOS activity with no effect at all upon the secretion of PGE(2) but has a strong inhibitory effect upon MCP-1 and IL-10 secretion and gene expression. Secretion and gene expression of TNF-alpha and IL-6 were moderately inhibited whereas IL-8 and IL-1beta were not altered. We conclude that BHMC selectively inhibits the synthesis of several inflammatory mediators. BHMC should be considered a promising drug lead for preclinical and further pharmacological studies.

A bioassay-guided investigation of Melicope ptelefolia Champ ex Benth (Rutaceae) resulted in the identification of an acyphloroglucinol, 2,4,6-trihydroxy-3-geranylacetophenone or tHGA, as the active principle inhibiting soybean 15-LOX. The anti-inflammatory action was also demonstrated on human leukocytes, where the compound showed prominent inhibitory activity against human PBML 5-LOX, with an IC(50) value of 0.42 μM, very close to the effect produced by the commonly used standard, NDGA. The compound concentration-dependently inhibited 5-LOX product synthesis, specifically inhibiting cysteinyl leukotriene LTC(4) with an IC(50) value of 1.80 μM, and showed no cell toxicity effects. The anti-inflammatory action does not seem to proceed via redox or metal chelating mechanism since the compound tested negative for these bioactivities. Further tests on cyclooxygenases indicated that the compound acts via a dual LOX/COX inhibitory mechanism, with greater selectivity for 5-LOX and COX-2 (IC(50) value of 0.40 μM). The molecular features that govern the 5-LOX inhibitory activity was thus explored using in silico docking experiments. The residues Ile 553 and Hie 252 were the most important residues in the interaction, each contributing significant energy values of -13.45 (electrostatic) and -5.40 kcal/mol (electrostatic and Van der Waals), respectively. The hydroxyl group of the phloroglucinol core of the compound forms a 2.56Å hydrogen bond with the side chain of the carboxylate group of Ile 553. Both Ile 553 and Hie 252 are crucial amino acid residues which chelate with the metal ion in the active site. Distorting the geometry of these ligands could be the reason for the inhibition activity shown by tHGA. The molecular simulation studies supported the bioassay results and served as a good model for understanding the way tHGA binds in the active site of human 5-LOX enzyme.