Abstract
Flavonoids are polyphenols with broad known pharmacological properties. A series of 2,3-dihydroflavanone derivatives were thus synthesized and investigated for their anti-inflammatory activities. The target flavanones were prepared through cyclization of 2′-hydroxychalcone derivatives, the later obtained by Claisen–Schmidt condensation. Since nitric oxide (NO) represents an important inflammatory mediator, the effects of various flavanones on the NO production in the LPS-induced RAW 264.7 macrophage were assessed in vitro using the Griess test. The most active compounds were flavanone (4G), 2′-carboxy-5,7-dimethoxy-flavanone (4F), 4′-bromo-5,7-dimethoxy-flavanone (4D), and 2′-carboxyflavanone (4J), with IC50 values of 0.603, 0.906, 1.030, and 1.830 µg/mL, respectively. In comparison, pinocembrin achieved an IC50 value of 203.60 µg/mL. Thus, the derivatives synthesized in this work had a higher NO inhibition capacity compared to pinocembrin, demonstrating the importance of pharmacomodulation to improve the biological potential of natural molecules. SARs suggested that the use of a carboxyl-group in the meta-position of the B-ring increases biological activity, whereas compounds carrying halogen substituents in the para-position were less active. The addition of methoxy-groups in the meta-position of the A-ring somewhat decreased the activity. This study successfully identified new bioactive flavanones as promising candidates for the development of new anti-inflammatory agents.
Highlights
Inflammation is involved in many diseases, such as infectious diseases, chronic inflammation, asthma, diabetes, neurodegenerative diseases, coronaviruses, and cancer [1,2]
Anti-inflammatory treatments are mostly based on corticoids or non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin (2-acetyloxybenzoic acid) and ibuprofen (2-[4-(2-methylpropyl)phenyl]propanoic acid)
The photochemical route was investigated as a milder approach [24]; the efficiency of photocyclization is known to depend on the irradiation wavelength [25]
Summary
Inflammation is involved in many diseases, such as infectious diseases, chronic inflammation, asthma, diabetes, neurodegenerative diseases, coronaviruses, and cancer [1,2]. Long-term therapy involving these common pharmaceuticals leads to severe side effects such as gastrointestinal ulceration and bleeding, osteoporosis, hypertension, and glaucoma. Macrophages are essential in the inflammatory process, and some bacterial endotoxins, such as lipopolysaccharide (LPS), allow their activation [4]. Nitric oxide (NO) is an inflammatory mediator that influences various biological processes [5]. NO can exhibit cytotoxicity and tissue damage. Inhibition of this mediator can provide therapeutic effects and allow measurement of the degree of inflammation. Natural products such as the sesquiterpene yomogin isolated from Artemisia princeps or Ginkgo biloba extract are known to inhibit NO production [6,7]
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