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.

Synthesis of 16 New Hybrids from Tetrahydropyrans Derivatives and Morita-Baylis-Hillman Adducts: In Vitro Screening against Leishmania donovani.

Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala-aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The Morita-Baylis-Hillman adducts (MBHAs) are being explored as drug candidates against several diseases, one of them being leishmaniasis. We present here the design, synthesis and in vitro screening against Leishmania donovani of sixteen new molecular hybrids from analgesic/antiinflammatory tetrahydropyrans derivatives and Morita-Baylis-Hillman adducts. First, acrylates were synthesized from analgesic/anti-inflammatory tetrahydropyrans using acrylic acid under TsOH as a catalyst (70-75% yields). After the 16 new MBHAs were prepared in moderate to good yields (60-95%) promoted by microwave irradiation or low temperature (0 °C) in protic and aprotic medium. The hybrids were evaluated in vitro on the promastigote stage of Leishmania donovani by determining their inhibitory concentrations 50% (IC50), 50% hemolysis concentration (HC50), selectivity index (HC50/IC50,), and comparing to Amphotericin B, chosen as the anti-leishmanial reference drug. The hybrid which presents the bromine atom in its chemical structure presents high leishmanicide activity and the high selectivity index in red blood cells (SIrb > 180.19), compared with the highly-toxic reference drug (SIrb = 33.05), indicating that the bromine hybrid is a promising compound for further biological studies.

Synthesis and In Vitro Anti Leishmania amazonensis Biological Screening of Morita-Baylis-Hillman Adducts Prepared from Eugenol, Thymol and Carvacrol.

Leishmaniasis represents a series of severe neglected tropical diseases caused by protozoa of the genus Leishmania and is widely distributed around the world. Here, we present the syntheses of Morita-Baylis-Hillman adducts (MBHAs) prepared from eugenol, thymol and carvacrol, and their bioevaluation against promastigotes of Leishmania amazonensis. The new MBHAs are prepared in two steps from essential oils in moderate to good yields and present IC50 values in the range of 22.30-4.71 µM. Moreover, the selectivity index to the most potent compound is very high (SIrb > 84.92), far better than that of Glucantime® (SIrb 1.39) and amphotericin B (SIrb = 22.34). Conformational analysis were carried out at the M062X//6-31+G(d,p) level of theory to corroborate a hypothesis about the nitroaromatic bioreduction mechanism.

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 Inflammatory Process In vitro and In vivo.

Morita-Baylis-Hillman adducts (MBHA) are synthetic molecules with several biological actions already described in the literature. It has been previously described that adduct 2-(3-hydroxy-2-oxoindolin-3-yl)acrylonitrile (ISACN) has anticancer potential in leukemic cells. Inflammation is often associated with the development and progression of cancer. Therefore, to better understand the effect of ISACN, this study aimed to evaluate the anti-inflammatory potential of ISACN both in vitro and in vivo. Results demonstrated that ISACN negatively modulated the production of inflammatory cytokines IL-1ß, TNF-α, and IL-6 by cultured macrophages. In vivo, ISACN 6 and 24 mg/kg treatment promoted reduced leukocyte migration, especially neutrophils, to the peritoneal cavity of zymosan-challenged animals. ISACN displays no anti-edematogenic activity, but it was able to promote a significant reduction in the production of inflammatory cytokines in the peritoneal cavity. These data show, for the first time, that MBHA ISACN negatively modulates several aspects of the inflammatory response, such as cell migration and cytokine production in vivo and in vitro, thus having an anti-inflammatory potential.