Psoriasis is a chronic inflammatory disease and is difficult to cure. In this work, a series of novel chrysin derivatives have been designed and prepared while evaluating anti-inflammatory activities in vitro and in vivo. In vitro, RAW264.7 cells were used to detect the inflammatory activities at first, and compounds 4h, 4k, and 4o significantly decreased the levels of NO, TNF-α, and IL-6. In particular, compound 4o showed superior anti-inflammatory activities than other compounds. Moreover, compound 4o decreased the level of IL-17A in LPS-induced HaCaT cells in vitro. The effect and mechanism of anti-inflammatory activities on psoriasis were determined by imiquimod (IMQ)-induced psoriasis-like mice in vivo. Compound 4o deduced the level of IL-6, IL-17A, IL-22, IL-23, and TNF-α, and showed potent anti-psoriasis activity. Further mechanism study suggested that compound 4o could improve the skin inflammation of psoriasis by inhibiting the NF-κB and STAT3 signaling pathways.

This study introduces newly discovered chrysin derivatives that show potential as candidate molecules for treating inflammatory bowel disease (IBD). Compound 4b, among the synthesized compounds, displayed significant inhibitory effects on monocyte adhesion to colon epithelium induced by TNF-α, with an IC50 value of 4.71 μM. Further mechanistic studies demonstrated that 4b inhibits the production of reactive oxygen species (ROS) and downregulates the expression of ICAM-1 and MCP-1, key molecules involved in monocyte-epithelial adhesion, as well as the transcriptional activity of NF-κB. In vivo experiments have shown that compound 4b exhibits a dose-dependent inhibition of 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats, thereby validating its effectiveness as a colitis inhibitor in animal models. These results indicate that 4b shows considerable promise as a therapeutic agent for managing IBD.

In this study, we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly (ADP-ribose) polymerase 1 (PARP1). Among these derivatives, compound 5d emerged as the most effective chrysin-based inhibitor of PARP1, with an IC50 value of 108 nmol·L-1. This compound significantly inhibited the proliferation and migration of breast cancer cell lines HCC-1937 and MDA-MB-436 by inducing DNA damage. Furthermore, 5d induced apoptosis and caused an extended G1/S-phase in these cell lines. Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1. In vivo, in a xenograft model, 5d effectively reduced tumor growth by downregulating PARP1 expression. Overall, compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer.

Twenty-three chrysin derivatives were designed and synthesized by alkylation and bromination reactions. Their structures were confirmed by NMR and mass spectrometry, and their in vitro ⍺-glucosidase (AG) inhibitory activity was investigated. Chrysin derivatives except for 3a, 3b, 2q, and 2r, revealed better activity than the reference acarbose with moderate to very strong inhibition against AG. Notably, 2f, 2j, and 4 showed very strong and strong effects on AG ⍺-glucosidase inhibitory activity with IC50 values of 0.08, 3.47, and 2.97 μM, respectively. Simultaneously, enzyme kinetics study indicated that 2f was a competitive-type inhibitor, while 2j and 4 were mixed-type inhibitors.

With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer\' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1-4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by 1H NMR, 13C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on reactive oxygen species, Aβ1-42 aggregation (self-, Cu2+-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1-4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1-4 have also been synthesized. 1-4 selectively chelated Cu2+, Fe2+, Zn2+ and Al3+ ions, while had no chelating ability to other biometals. The copper complexes also showed good AChE, BuChE and reactive oxygen species inhibitory activities. Notably, the single crystals of 1-Cu(II) complex [Cu(C19H18NO4)2] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1-Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Aβ1-42 disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.

Alzheimer\'s disease (AD) is the most common type of dementia, the exact etiology of the disease has not been known yet. The use of single-target drugs limits the efficacy of drugs and has certain side effects. In this study, the \'hidden\' multi-target strategy was used in combination with chrysin\'s metal chelating site and rivastigmine\'s anti-cholinesterase pharmacophore to form an ester, which improves the hydrophobicity and protects the phenolic hydroxyl group at the same time. Four derivatives (1-4) were synthesized as the hidden multifunctional agents for AD therapy. Most of the compounds displayed good activities of anti-cholinesterase, antioxidant, appropriate blood brain barrier (BBB) penetration and certain inhibitory activity of β-amyloid (Aβ) aggregation. Compound 3 was demonstrated as the highest selective butyrylcholinesterase (BuChE) inhibitor and targeted both the catalytic active site (CAS) and the peripheral anion site (PAS). And it could be hydrolyzed by BuChE to release chrysin with good ability to chelate Cu2+ and Fe2+. At the same time, phenol fragment can exert its good antioxidant effect. Overall, these findings demonstrated that compound 3 might be considered as a potential hidden multifunctional candidate in the therapy of AD.

Multidrug resistance mechanism of microorganisms towards conventional antimicrobials nowadays faces a common health problem. So, searching and development of new antibacterials are in the frontier areas of biochemistry. Functionalizations of various natural products or synthesis of compounds through molecular modeling followed by virtual screening are the ways to obtain potential leads. Chrysin is one of the plant secondary metabolites and is ubiquitously present in majority of plants. It has multi-dimensional potentiality however, with a very low bioavailability causing a very low efficacy. Very few chrysin derivatives possessing antimicrobial activity with a low anti-biofilm efficacy have been found in the literature. Thus, it has been attempted to synthesize a series of new chrysin derivatives (CDs). In this study, twenty-two new derivatives have been synthesized via its 7-OH modulation and antibiofilm activity was evaluated against a model bacterium viz. Escherichia coli MTCC 40 (Gram negative). Eleven CDs coded as 2a, 2b, 2c, 2e, 2f, 2g, 2h, 2i, 3j, 3k and 3l have been found more potent compared to chrysin (precursor of CDs) against planktonic form of E. coli. Biofilm inhibition studies indicated a noteworthy results for 2a (93.57%), 2b (92.14%), 2f (92.14%) and 3l (93.57%) compared to chrysin (33.57%). E. coli motility was also highly restricted by 2a, 2b, 2f and 3l than chrysin at their sub-inhibitory concentrations. Solubility studies indicated an extended-release of 2a, 2b, 2f and 3l in physiological systems. Relatively higher bioavailability of 2a, 2b, 2f and 3l than chrysin was revealed from the dissolution experiments and was further validated through in silico ADME-based SAR analysis. Hence, this study is more interesting in regard to antibacterial potentiality of chrysin derivatives against Escherichia coli MTCC 40 (Gram negative). Thus, this article might be useful for further design and development of new leads in the context of biofilm-associated bacterial infections.

Chrysin amino acid derivatives were synthesized to evaluate for their antiproliferative activities. Among them, N-(7-((5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)valeryl)-L-leucine (8c) displayed the most remarkable inhibitory activities against MCF-7 cells with IC50 values of 16.6 μM. Preliminary mechanistic studies showed that 8c could inhibit the colony formation and migration of MCF-7 cells. Flow cytometry analysis demonstrated that 8c mediated cell apoptosis and the prolongation of cell cycle progression in G1/S-phase against MCF-7 cells. Besides, 8c displayed the moderate inhibition against EGFR. Western blot assay suggested that 8c significantly inhibited EGFR phosphorylation. Molecular docking showed that 8c can bind the EGFR kinase well.

OBJECTIVE: Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity.
METHODS: A series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score ≥ 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using 1H-NMR, 13C-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin.
RESULTS: The data depicted a 3.2-fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells.
CONCLUSIONS: The present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.

The skin is an important physiological barrier against external stimuli, such as ultraviolet radiation (UV), xenobiotics, and bacteria. Dermal inflammatory reactions are associated with various skin disorders, including chemical-induced irritation and atopic dermatitis. Modulation of skin inflammatory response is a therapeutic strategy for skin diseases. Here, we synthesized chrysin-derivatives and identified the most potent derivative of Compound 6 (CPD 6). We evaluated its anti-inflammatory effects in vitro cells of macrophages and keratinocytes, and in vivo dermatitis mouse models. In murine macrophages stimulated by lipopolysaccharide (LPS), CPD 6 significantly attenuated the release of inflammatory mediators such as nitric oxide (NO) (IC50 for NO inhibition: 3.613 μM) and other cytokines. In cultured human keratinocytes, CPD 6 significantly attenuated the release of inflammatory cytokines induced by the combination of IFN-γ and TNF-α, UV irradiation, or chemical irritant stimulation. CPD 6 inhibited NFκB and JAK2/STAT1 signaling pathways, and activated Nrf2/HO-1 signaling. In vivo relevancy of anti-inflammatory effects of CPD 6 was observed in acute and chronic skin inflammation models in mice. CPD 6 showed significant anti-inflammatory properties both in vitro cells and in vivo dermatitis animal models, mediated by the inhibition of the NFκB and JAK2-STAT1 pathways and activation of Nrf2/HO-1 signaling. We propose that the novel chrysin-derivative CPD 6 may be a potential therapeutic agent for skin inflammation.