Biological Activities of Morita-Baylis-Hillman Adducts (MBHA).

BACKGROUND: The Morita-Baylis-Hillman reaction (MBHR) is considered one of the most powerful and versatile methodologies used for carbon-carbon bond formation. The reaction is defined as the condensation between an electrophilic carbon sp² and the α position of an olefin, carrying an electron-withdrawing group, in the presence of a catalyst. The advantages of the reaction are the high atom economy and mild reaction conditions. Under ideal conditions, this reaction leads to the formation of multifunctional products, called Morita-Baylis-Hillman adducts (MBHA), a class of relevant molecules that exhibit a variety of biological activities. OBJECTIVE: Considering the importance of these compounds, this review brought together several studies regarding the biological activities of MBHA, to point out the use of these molecules as future therapeutic agents. METHODS: We searched for scientific articles available in the main databases, published between 1999 and 2022, using the descriptors: Morita-Baylis-Hillman adducts, Morita-Baylis-Hillman reaction, biological activity, and biological potentiality. RESULTS: Thirty-five articles showed the variety of biological activities of MBHA, including molluscicidal, antitumor, herbicidal, and fungicidal, antileishmanial, antioxidant, antimalarial, anti-tumor inflammatory, vasorelaxant, antichagasic, antimicrobial, and anti-inflammatory activities. CONCLUSION: Therefore, these compounds are promising candidates to become drugs for the treatment of a variety of diseases, following further studies to understand the effective mechanisms of action of MBHA.

Morita-Baylis-Hillman adduct 2-(3-hydroxy-2-oxoindolin-3-yl)acrylonitrile (ISACN) modulates the inflammatory process during LPS-induced acute lung injury.

BACKGROUND: Despite its homeostatic role, inflammation is involved in several pathologies, such as acute lung injury. Morita-Ballys-Hilman adducts (MBHA) are a group of synthetic molecules and present a wide range of biological activities, including anti-inflammatory action. Thus, this study aimed to assess whether ISACN, an MBHA, modulates inflammation during acute lung injury induced by lipopolysaccharide (LPS). METHODS: BALB/c mice were intraperitoneally treated with 24 mg/kg ISACN and challenged with LPS (2.5 mg/kg). On bronchoalveolar lavage fluid (BALF), we assessed the total and differential leukocyte count and measurement of protein leakage, cytokines (IL-1ß, IL-6, and TNF-α), and chemokine (CXCL-1). Additionally, lung histopathology was also performed (H&E staining). In vitro studies were conducted with peritoneal macrophages to assess the possible mechanism of action. They were cultured in the presence of ISACN (5 and 10 µM) and stimulated by LPS (1 µg/mL). RESULTS: ISACN reduced neutrophil migration, protein leakage, and inflammatory cytokines (IL-1ß, IL-6, and TNF-α) without interfering with the production of CXCL1. In addition, ISACN caused a decrease in LPS-induced lung injury as evident from histopathological changes. In peritoneal macrophages, ISACN diminishes the nitric oxide and cytokine levels (IL-1ß, IL-6, and TNF-α). The treatment with ISACN (10 µM) also reduced LPS-induced TLR4, CD69, iNOS overexpression, and the LPS-induced ERK, JNK, and p38 phosphorylation. CONCLUSION: Thus, this work showed for the first time the immunomodulatory action of MBHA in LPS-induced acute lung injury and provided new evidence for the mechanisms related to the anti-inflammatory effect of ISACN.

4-Carvomenthenol, a monoterpene of essential oils, and its underlying effects on anti-inflammatory activity and immediate hypersensitivity reaction

Abstract The monoterpene 4-carvomenthenol (Carvo) is found in essential oils of plant. Here, we evaluate the Carvo oral pretreatment in acute inflammatory experimental models and in silico molecular docking. Mice pretreated with Carvo were challenged and submitted to the protocols: paw edema, peritonitis, scratching behavior and anaphylactic shock reaction. Besides, we used histamine H1 receptor, cyclooxygenases (COX-1 and COX-2) and phospholipase A2, as targets for molecular docking analysis. Carvo inhibited the carrageenan-induced paw edema and decreased the peritoneal influx of polymorphonuclear cells on carrageenan-challenged mice without interfering with the mononuclear cell influx. Moreover, Carvo diminished the histamine, PGE2 and compound 48/80 induced paw edematogenic effect. The monoterpene also diminished the mice scratching behavior and, surprisingly, avoided the animal death caused by compound 48/80 in 30 min. Through the docking analysis, Carvo showed favorable binding energy to the histamine H1 receptor. This study demonstrates that Carvo attenuated the allergic inflammatory process, decreasing edema, cell migration, activation of mast cells and the histamine release, probably due to interaction of Carvo with the histamine H1 receptor, ameliorating the itching and the anaphylactic shock reaction. Therefore, the results of this study indicate that Carvo has anti-inflammatory properties by reducing the histamine effects.

MHTP, a synthetic tetratetrahydroisoquinoline alkaloid, attenuates lipopolysaccharide-induced acute lung injury via p38MAPK/p65NF-κB signaling pathway-TLR4 dependent.

INTRODUCTION: This study investigated the mechanism of action of a synthetic tetrahydroisoquinoline alkaloid, MHTP, in an experimental model of acute lung injury (ALI) in two distinct moments: 72 h and 10 days. METHODOLOGY: To realize this study, 2.5 mg/kg of lipopolysaccharide (LPS) was intranasally administered in BALB/c mice, and nasal instillation of MHTP (1.25; 2.5; 5.0; 10 or 20 mg/kg) was administrated at 1, 24, and 48 h after LPS challenge. The data were statistically analyzed and p < 0.05 was considered statistically significant. RESULTS: MHTP treatment (2.5, 5.0, 10 or 20 mg/kg) significantly decreased neutrophil migration into the bronchoalveolar lavage fluid (BALF), tissue inflammatory cell infiltration, edema, and hemorrhage as well as collagen fiber deposition on the perialveolar regions at both moments. TNF-α and IL-6 levels were significantly diminished in the MHTP-treated animals at 72 h and maintained them, at a basal level, at 10-day observation. These effects of MHTP are due to downregulating p38MAPkinese/p65NFκB signaling pathway-TLR4 dependent. Also, the MHTP treatment promoted a survival rate at 100% and improved their body weights during the 10-day observation. Unlike, the LPS group (non-treated LPS challenged animals) presented less than 50% of surviving rate at 72 h and the animals that survived did not improve their physiological state at 10-day observation. CONCLUSIONS: These data showed for the first time the beneficial and effective activity of a nasal treatment with a synthetic tetrahydroisoquinoline alkaloid on an experimental model of ALI and pointed out the molecular mechanism related to it.

Toxicological evaluation in silico and in vivo of secondary metabolites of Cissampelos sympodialis in Mus musculus mice following inhalation.

The ethanolic extract of the leaves of Cissampelos sympodialis showed great pharmacological potential, with inflammatory and immunomodulatory activities, however, it showed some toxicological effects. Therefore, this study aims to verify the toxicological potential of alkaloids of the genus Cissampelos through in silico methodologies, to develop a method in LC-MS/MS verifying the presence of alkaloids in the infusion and to evaluate the toxicity of the infusion of the leaves of C. sympodialis when inhaled by Swiss mice. Results in silico showed that alkaloid 93 presented high toxicological potential along with the products of its metabolism. LC-MS/MS results showed that the infusion of the leaves of this plant contained the alkaloids warifteine and methylwarifteine. Finally, the in vivo toxicological analysis of the C. sympodialis infusion showed results, both in biochemistry, organ weights and histological analysis, that the infusion of C. sympodialis leaves presents a low toxicity.