Morita-Baylis-Hillman adducts derived from thymol: synthesis, in silico studies and biological activity against Giardia lamblia.

Giardiasis is a neglected disease, and there is a need for new molecules with less side effects and better activity against resistant strains. This work describes the evaluation of the giardicidal activity of thymol derivatives produced from the Morita-Baylis-Hillman reaction. Thymol acrylate was reacted with different aromatic aldehydes, using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst. Eleven adducts (8 of them unpublished) with yields between 58 and 80% were obtained from this reaction, which were adequately characterized. The in silico prediction showed theoretical bioavailability after oral administration as well as antiparasitic activity against Giardia lamblia. Compound 4 showed better biological activity against G. lamblia. In addition to presenting antigiardial activity 24 times better than thymol, this MBHA was obtained in a short reaction time (3 h) with a yield (80%) superior to the other investigated molecules. The molecule was more active than the precursors (thymol and MBHA 12) and did not show cytotoxicity against HEK-293 or HT-29 cells. In conclusion, this study presents a new class of drugs with better antigiardial activity in relation to thymol, acting as a basis for the synthesis of new bioactive molecules. Molecular hybridization technique combined with the Morita-Baylis-Hillman reaction provided new thymol derivatives with giardicidal activity superior to the precursor molecules.

Synthesis, anti-proliferative activity, theoretical and 1H NMR experimental studies of Morita-Baylis-Hillman adducts from isatin derivatives.

Quaternary or spirocyclic 3-substituted-3-hydroxy-2-oxindole is considered a privileged scaffold. In other words, it is a molecular core present on several compounds with a wide spectrum of biological activities. Among its precursors, activated ketones (isatin nucleus) can be used as interesting starting points to Morita-Baylis-Hillman adducts derivatives, a class of compounds with good cytotoxic potential. In this paper, we present the synthesis, anti-proliferative activity against lung cancer cell line and a theoretical conformational study of 21 of Morita-Baylis-Hillman adducts from isatin derivatives, by DFT quantum chemical calculations, followed by a SAR and QSAR analysis. Besides, an efficient synthetic protocol and good biological activity profile were highlighted interesting observations about 1H NMR experimental spectra, molecular modeling results and crystallographic data available.

Biological activity of Morita-Baylis-Hillman adduct homodimers in L. infantum and L. amazonensis: anti-Leishmania activity and cytotoxicity.

This study is a report on the anti-Leishmania activity of Morita-Baylis-Hillman (MBH) homodimers adducts against the promastigote and axenic amastigote forms of Leishmania (Leishmania) infantum and Leishmania (Leishmania) amazonensis and on the cytotoxicity of these adducts to human blood cells. Both studied homodimers, MBH 1 and MBH 2, showed activity against the promastigote forms of L. infantum and L. amazonensis, which are responsible for visceral and cutaneous leishmaniasis, respectively. Additionally, the homodimers presented biological activity against the axenic amastigote forms of these two Leishmania species. The adducts exhibited no hemolytic activity to human peripheral blood mononuclear cells or erythrocytes at the tested concentrations and achieved higher selectivity indices than amphotericin B. Evaluation of cell death by apoptosis revealed that the homodimers had better apoptosis/necrosis profiles than amphotericin B in the promastigote forms of both L. infantum and L. amazonensis. In conclusion, these Morita-Baylis-Hillman adducts had anti-Leishmania activity in an in vitro model and may thus be promising molecules in the search for new drugs to treat leishmaniasis.

Morita-Baylis-Hillman Adducts Display Anti-Inflammatory Effects by Modulating Inflammatory Mediator Expression in RAW264.7 Cells.

Inflammatory response plays an important role not only in the normal physiology but also in pathologies such as cancers. The Morita-Baylis-Hillman adducts (MBHA) are a novel group of synthetic molecules that have demonstrated many biological activities against some parasitic cells such as Plasmodium falciparum, Leishmania amazonensis, and Leishmania chagasi, and antimitotic activity against sea urchin embryonic cells was also related. However, little is known about the mechanisms induced by MBHA in inflammatory process and its relation with anticancer activity. The present work investigated the cytotoxicity of three MBHA derivatives (A2CN, A3CN, and A4CN), on human colorectal adenocarcinoma, HT-29 cells, and their anti-inflammatory activities were examined in lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells, being these derivatives potentially cytotoxic to HT-29 cells. Coincubation with A2CN, A3CN, or A4CN and LPS in RAW264.7 cells inhibited NO production, as well as the production of reactive oxygen species (ROS) was also repressed. The mRNA expressions of IL-1ß and IL-6 were significantly downregulated by such MBHA compounds in RAW264.7 cells, but only A2CN was able to inhibit the COX-2 gene expression. We also showed that MBHA compounds decreased almost to zero the production of IL-1ß and IL-6. These findings display that such MBHA compounds exhibit anticancer and anti-inflammatory activities.

Synthesis and activity of novel homodimers of Morita-Baylis-Hillman adducts against Leishmania donovani: A twin drug approach.

It is reported here the synthesis of novel Homodimers 12-19 of Morita-Baylis-Hillman adducts (MBHA) from one-pot Morita-Baylis-Hillman Reaction (MBHR) between aromatic aldehydes as eletrophiles and ethylene glycol diacrylate as Michael acceptor (35-94% yields) using cheap and green conditions. The bioactivities were evaluated against promastigote form of Leishmania donovani. All homodimers showed to be more potent than corresponding monomers. It is worth highlighting that the halogenated homodimers 17 and 18 (0.50µM) is almost 400 times more active than the corresponding monomer 10 and 1.24 times more potent than the second-line drug amphotericin B (0.62µM). Moreover, the selectivity index to 18 is very high (SIrb>400) far better than amphotericin B (SIrb=18.73). This is the first report of twin drugs strategy applied on Morita-Baylis-Hillman adducts.

Trypanosoma cruzi cell death induced by the Morita-Baylis-Hillman adduct 3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile).

Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a serious health concern due to the lack of effective vaccines or satisfactory treatment. In the search for new compounds against this neglected disease, we have previously demonstrated that the compound 3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile) (MBHA3), derived from the Morita-Baylis-Hillman reaction, effectively caused a loss of viability in both the epimastigote and trypomastigote forms. However, the mechanisms of parasite death elicited by MBHA3 remain unknown. The aim of this study was to better understand the morphophysiological changes and the mechanism of cell death induced by MBHA3 treatment on T. cruzi. To perform this analysis, we used confocal microscopy and flow cytometry to monitor the fluorescent probes such as annexin-V/propidium iodide (AV/PI), calcein-AM/ethidium homodimer (CA/EH), acridine orange (AO) and rhodamine 123 (Rho 123). Lower concentrations of MBHA3 led to alterations in the mitochondrial membrane potential and AO labeling, but did not decrease the viability of the epimastiogote forms, as determined by the CA/EH and AV/PI assays. Conversely, treatment with higher concentrations of MBHA3 led to extensive plasma membrane damage, loss of mitochondrion membrane potential, DNA fragmentation and acidification of the cytoplasm. Our findings suggest that at higher concentrations, MBHA3 induces T. cruzi epimastigote death by necrosis in a mitochondrion-dependent manner.

Morita-Baylis-Hillman adducts: biological activities and potentialities to the discovery of new cheaper drugs.

This review aims to present by the first time the Morita-Baylis-Hillman adducts (MBHA) as a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs. Now, most these compounds can be prepared fast and on a single synthetic step (one-pot reaction) in high yields and using ecofriendly synthetic protocols. We highlight here the aromatic MBHA, which have shown diverse biological activities as anti-Leishmania chagasi and Leishmania amazonensis (parasites that cause cutaneous and visceral leishmaniasis), anti-Trypanosoma cruzi (parasite that cause Chagas disease), anti-Plasmodium falciparum and Plasmodium berghei (parasites that cause malaria), lethal against Biomphalaria glabrata (the snail transmitter of schistosomiasis), antibacterial, antifungal, herbicide and actives against some human tumor cell lines. Understanding of the biological mechanisms of action of this new class of molecules is still in the infancy stage. However, we report here which has been described to date on the possibilities of biological mechanisms of action, and we present new analyzes based on literature in this area. The academic and industrial interest in selecting green and cheaper experiments to the drugs development has been the prime mover of the growth on the subject.