Evidence that the anti‐inflammatory effect of 4‐aryl‐4H‐chromenes is linked to macrophage repolarization

Abstract

The inflammatory response is a common feature of many pathological conditions, and there is urgent necessity for new substances that minimize the harmful effects of inflammation. Chromenes represent a class of compounds with multiple pharmacological actions that have already been described and may be potential candidates for studies of therapeutic action. This study aimed to test novel 4‐aryl‐4H‐chromene‐derived molecules in an in vitro model of inflammation using lipopolysaccharide (LPS)‐induced Raw 264.7 cells. Seven compounds derived from 4‐aryl‐4H‐chromene were tested on Raw 264.7 cells to evaluate their cytotoxic effects. Next, the effect of the selected compounds on the pro‐inflammatory mediators (tumor necrosis factor‐alpha [TNF‐α], monocyte chemoattractant protein‐1 [MCP‐1], interleukin [IL]‐6) and on the anti‐inflammatory mediators (IL‐10 and IL‐13) was analyzed, and finally, the effect of the compounds on macrophage apoptosis and expression of surface receptors (toll‐like receptor 4 [TLR‐4] and mannose) was evaluated. The results of this study demonstrated that changes in the molecular structure of 4‐aryl‐4H‐chromene altered its cytotoxic profile. Therefore, derivatives that showed safe results were selected for further analyses (named compounds: 4–6). In these experiments, the compounds were able to decrease nitric oxide (NO) levels and production of MCP‐1, IL‐6, IL‐10, and IL‐13. Furthermore, these derivatives were effective in reducing macrophage apoptosis and the expression of surface receptors, as TLR‐4/CD284. Moreover, compounds 5 and 6 also were effective in increasing mannose receptor (CD206) expression. The results indicate, for the first time to our knowledge, that the anti‐inflammatory effect produced by chromenes is linked to macrophage repolarization (M1 to M2).

Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

“…This finding reinforces the affirmation that 1,4‐DHP derivatives exert their anti‐inflammatory effects by changing the macrophage phenotype, Choe et al demonstrated that murine macrophages stimulated with LPS and pretreated with nifedipine led to a significant increase in mRNA expression of Arg‐1, Ym‐1, FIZZ1, and TGF‐β, characteristic markers of polarization of M2‐type macrophages [14]. Our results show, in addition to the decrease in the levels of cytokines characteristic of M1 responses, an increase in the phagocytic activity of the macrophages, as well as an increase in the production of the anti‐inflammatory cytokine IL‐10, which is characteristic of the M2 phenotype [37, 38].…”

“…Our results show, in addition to the decrease in the levels of cytokines characteristic of M1 responses, an increase in the phagocytic activity of the macrophages, as well as an increase in the production of the antiinflammatory cytokine IL-10, which is characteristic of the M2 phenotype [37,38].…”

Interference in Macrophage Balance (M1/M2): The Mechanism of Action Responsible for the Anti-Inflammatory Effect of a Fluorophenyl-Substituted Imidazole

“…The test used a Rezarsurin solution (1.5 mg/mL) diluted in culture medium in contact with pretreated cells for 2 hr, with subsequent reading in fluorescence, using a wavelength of 530/590 nm in a Geminis™ XPS microplate spectrofluorometer (Molecular Devices, CA, USA). Based on these results, it was possible to determine the CC 10 value for the 2-fluorophenyl-imidazole, i.e., the concentration capable of killing 10% of the cell population, and consequently maintaining a viability of 90% [20,21]. This parameter was calculated through nonlinear regression analysis of the concentration logarithm as a function of the normalized response (percentage of cell viability) using GraphPad Prism ® version 8.0 (San Diego, CA, USA).…”

Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors

“… 30 , 31 The ubiquitous chromene framework is well known for several pharmacological activities like antifungal, 32 antimicrobial, 33 antiviral, 34 anti-allergic, 35 antiulcer, 36 and anti-inflammatory activities. 37 Furthermore, fused-chromene compounds are renowned to exhibit a wide range of therapeutic applications starting with antitumor, 38 antileishmanial, 39 antiproliferation, 40 anti-HIV agent, 41 and antioxidative applications. 42 The substituted side chains in the structural framework of benzopyran exhibited the pharmaceutical potential of coumarin-containing drugs, thus exploring their prominence in synthetic and clinical perspective.…”

“…The synthesis of efficient heterocyclic molecules with a natural product core and their exploration as therapeutic agents against human diseases have become an indispensable paradigm of clinical trials in modern drug development . Chromenes and coumarins are among the O-ring heterocycles with a benzopyrone skeleton and have gained the attention of pharmaceutical chemists for a number of years because of their therapeutic potential and biological significance. , The ubiquitous chromene framework is well known for several pharmacological activities like antifungal, antimicrobial, antiviral, anti-allergic, antiulcer, and anti-inflammatory activities . Furthermore, fused-chromene compounds are renowned to exhibit a wide range of therapeutic applications starting with antitumor, antileishmanial, antiproliferation, anti-HIV agent, and antioxidative applications .…”