Mário L. A. A. Vasconcellos

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.

Improved synthesis of seven aromatic Baylis-Hillman adducts (BHA): evaluation against Artemia salina Leach. and Leishmania chagasi.

We described a very efficient procedure to prepare seven aromatic compounds (1-7), a new class of antileishmanial substances, through Baylis-Hillman reaction (BHR). With one, all the Baylis-Hillman adducts were prepared in quantitative yields by reaction of the corresponding aromatic aldehydes in acrylonitrile at 0 degrees C in only 10-40min reaction time. We present our results about the toxicities of these compounds evaluated on the microcrustaceous Artemia salina Leach. and against promastigote Leishmania chagasi. All substances evaluated in this work have showed high bioactivity. The 3-hydroxy-2-methylene-3-(4-bromopheny)propanenitrile (4) (LC(50)=30.9 microg/mL on A. salina; IC(50)=25.2 microM on L. chagasi) was the most active compound evaluated on A. salina Leach. and on promastigote L. chagasi. The 2-[hydroxy(pyridin-4-yl)methyl]acrylonitrile (7) (LC(50)=30.9 microg/mL on A. salina Leach.; IC(50)=4.8 microg/mL on L. chagasi) was also a very active substance evaluated in this work on promastigote L. chagasi.

Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach.

The chalcone-like series 1a-1g was efficiently synthesized from Morita-Baylis-Hillman reaction (52-74% yields). Compounds 1a-1g were designed by molecular hybridization based on the anti-inflammatory drug methyl salicylate (3) and the antileishmanial moiety of the Morita-Baylis-Hillman adducts 2a-2g. The 1a-1g compounds were much more actives than precursor series 2a-2g, for example, IC(50)=7.65 μM on Leishmania amazonensis and 10.14 μM on Leishmania chagasi (compound 1c) when compared to IC(50)=50.08 μM on L. amazonensis and 82.29 μM on L. chagasi (compound 2c). The IC(50) values of compound 3 (228.49 μM on L. amazonensis and 261.45 μM on L. chagasi) and acryloyl salicylate 4 (108.50 μM on L. amazonensis and 118.83 μM on L. chagasi) were determined here, by the first time, on Leishmania.

Efficient synthesis of 16 aromatic Morita-Baylis-Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi.

Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0°C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC₅₀ values of 6.88μgmL⁻¹ and 11.06μgmL⁻¹ respectively on L. amazonensis; 9.58μgmL⁻¹ and 14.34μgmL⁻¹ respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds.

3-Hydroxy-2-methylene-3-(4-nitrophenylpropanenitrile): A new highly active compound against epimastigote and trypomastigote form of Trypanosoma cruzi

We have synthesized the Morita-Baylis-Hillman adduct (MBHA) 3-hydroxy-2-methylene-3-(4-nitrophenyl)-propanenitrile (3) in quantitative yield and evaluated on Trypanosoma cruzi epimastigote and bloodstream trypomastigote forms. Compound 3 strongly inhibited epimastigote growth, with IC(50)/72hof 28.5 microM and also caused intense trypomastigotes lysis, with an IC(50)/24h of 25.5 microM. Ultrastructural analysis showed significant morphological changes on both parasite forms treated with 3, including increase of cell volume and rounding of cell body as well as intense intracellular disorganization. Morphological changes indicative of apoptosis, autophagy or necrosis were observed in most affected cells. Docking calculations of 1, 2 and 3 pointed out the possibility of T. cruzi Farnesyl Pyrophosphate Synthase (TcFPPS) enzyme inhibition in 3 mechanism of action.

Revisiting the Origin of the Preferential p-p Stacking Conformation of the (+)-8-Phenylmenthyl Acrylate

1 H NMR experimental data which show the stacking conformation of 2 (2S) is more stable that trans conformation (2T) and the stacking conformation of 3 (3S) is less stable that trans conformation (3T). After that, geometrical and energetic features of the intermolecular complex benzene…methylacrylate (4) have also been studied using MPW1B95 method. From our results, we have noticed that both steric and dispersion effects play a key role in the conformational equilibrium of 2.

A reação de ciclização de prins: uma estratégia eficiente para síntese estereosseletiva de anéis tetraidropirânicos substituídos

THE PRINS CYCLIZATION REACTION: AN EFFICIENT STRACTEGY FOR THE STEREOSELECTIVE SYNTHESIS OF SUBSTITUTED TETRAHYDROPYRAN RINGS. The Prins cyclization reaction has significantly advanced in the last years as demonstrated by a number of applications described in the literature. The objective of this report is to introduce this powerful synthetic methodology to the undergraduate and graduated student, since it is rarely presented in an organic synthesis formal course. This reaction is, in some cases, the methodology of choice for the preparation of natural products or drugs that present the tetrahydropyrane moiety in their structures. In this report we show some aspects of this reaction, including mechanism, scope and limitations.

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.

Correlation between electrochemical and theoretical studies on the leishmanicidal activity of twelve Morita-Baylis-Hillman adducts

Enzymatic bioreduction of nitro groups plays an important role on the activity of biologically active nitroaromatic compounds. Electrochemical methods are useful tools to simulate in vivo metabolic processes. This work presents electrochemical studies in aprotic media (N, N-dimethylformamide (DMF) plus tetrabutylammonium perchlorate (TBAP) 0.1 mol L-1) using cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square wave voltammetry (SWV) of twelve Morita-Baylis-Hillman adducts (MBHA) with significant leishmanicidal activity. To facilitate the analysis, the molecules were grouped in four classes according to the side chain. CV studies show three up to four reduction waves, in which the first two waves are related to nitro group reduction. The other waves (presenting more negative potential) refer to the reduction of the α,β-unsaturated carbonyl or to the nitrile activated olefin side-chain. Ortho adducts present facilitated reduction in comparison to the other isomers (meta and para) possibly due to hydrogen bond formation between the benzylic-OH and the nitro group, which stabilizes the reduction product (anion radical nitro) more efficiently than the original compound. Ortho derivatives also present higher leishmanicidal activity upon comparison to the other derivatives of each class. Conformational studies using HF/6-31+G(d)/PCM as a calculation level highlight this effect. Molecular hardness (N) and atomic charges (QN) values corroborate the obtained experimental data.

Design, Prins-cyclization reaction promoting diastereoselective synthesis of 10 new tetrahydropyran derivatives and in vivo antinociceptive evaluations

We described in this article the very efficient 2,6-cis ou 2,4,6-cis diastereoselective synthesis (2 or 3 steps, 62-65% global yields) from Prins-cyclization reaction as synthetic key-step to tetrahydropyran rings construction of 10 new congeners compounds (3-12) designed from Naproxen structure. These tetrahydropyran derivatives were in vivo bioevaluated on antinociceptive effect in the acetic acid-induced abdominal writhing test, the tail-flick test, the rota-rod performance and open field tests. All new compounds showed greater antinociceptive activity compared to compound 1a, an analgesic tetrahydropyran derivative previously described by us. We can detach the high activity of tetrahydropyran derivative 10 which presented 87.5% inhibition (14% inhibition was presented by 1a) in the acetic acid-induced abdominal writhing test. Besides that the tail-flick tests indicate compounds 7 and 10 as the most actives. All these new compounds showed no toxicity in mice in all biologically studied models.