RESUMEN
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 Eleven adducts (8 of them unpublished) with yields between 58 and 80% were obtained from this reaction, which were adequately characterized.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.
Asunto(s)
Giardia lamblia , Timol , Aldehídos , Catálisis , Células HEK293 , Humanos , Timol/farmacologíaRESUMEN
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.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Técnicas de Química Sintética , Isatina/química , Isatina/farmacología , Modelos Teóricos , Espectroscopía de Protones por Resonancia Magnética , Antineoplásicos/síntesis química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Isatina/análogos & derivados , Isatina/síntesis química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad CuantitativaRESUMEN
Tetrahydropyran (THP) rings are common in several natural products, therefore, various strategies are being developed to synthesize these rings. The present work described the study of a one-pot synthesis of 2,4,6-trisubstituted tetrahydropyran compounds promoted by the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6] through a Barbier-Prins reaction between allyl bromide and aldehydes. The use of [BMIM][PF6] gave Prins products from several aldehydes in good yields and reaction times. We also found that the anion, PF6-, accelerates the Barbier reaction when used alone, and the excess SnBr2 from the reaction conditions of the Barbier reaction leads to the formation of the THP rings, thus acting as a catalyst for Prins cyclization. Additionally, we demonstrate that ionic liquid can be recovered and reused five times in the preparation of 4-bromo-tetrahydro-2,6-diphenyl-2H-pyran without significant yield loss.
Asunto(s)
Alcaloides de Berberina/síntesis química , Imidazoles/química , Líquidos Iónicos/química , Catálisis , Técnicas de Química Sintética , Estructura MolecularRESUMEN
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.
Asunto(s)
Acrilonitrilo/análogos & derivados , Alcoholes Bencílicos/farmacología , Muerte Celular/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Trypanosoma cruzi/efectos de los fármacos , Acrilonitrilo/farmacología , Acrilonitrilo/uso terapéutico , Alcoholes Bencílicos/uso terapéutico , Membrana Celular/efectos de los fármacos , Enfermedad de Chagas/parasitología , Citoplasma/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microscopía Confocal , NitrilosRESUMEN
In the present work we described improvements in the 1-7 antiparasitic Morita-Baylis-Hillman Adducts synthesis and their antimitotic activity on sea urchin embryonic cells. The 2-[Hydroxy(2-nitrophenyl)methyl]acrylonitrile (1) and 2-[Hydroxy(4-bromophenyl) methyl]acrylonitrile (4) were the most effective compounds to block the progression to embryonic morula stage (EC(50) = 75.8 µM and 72.6 µM, respectively). Compounds 1 and 4 were also effective in blocking the first cell division but to a lesser extent. The 2-[Hydroxy(pyridin-4-yl)methyl]acrylonitrile (7) exhibited a strong inhibition of cell divisions and progression to the first cleavage and morula stage. Fluorescent dye extrusion assay suggests that these adducts are not ABC protein substrates, which confers an additional interest in these new class of potential anticancer drugs.
Asunto(s)
Antimitóticos/síntesis química , Antimitóticos/farmacología , Antiparasitarios/síntesis química , Antiparasitarios/farmacología , Embrión no Mamífero/citología , Erizos de Mar/embriología , Animales , Antimitóticos/química , Antiparasitarios/química , División Celular/efectos de los fármacos , Técnicas de Química Sintética , Leishmania/efectos de los fármacos , Mórula/citología , Mórula/efectos de los fármacosRESUMEN
We report the design, synthesis, in vitro evaluation against Leishmania amazonensis (IC(50)), cytotoxicity assays in macrophages (CC(50)), and selectivity index (SICC(50)/IC(50)) of sixteen new congeners aromatic Morita-Baylis-Hillman adducts 1-16. The 1-16 were prepared in good to excellent yields (58%-97%) from the "one pot" Morita-Baylis-Hillman Reaction between the aldehydes 29-36 and the acrylates 27 or 28 under DABCO as promoter. The MBHA 2-[Hydroxy(2-nitrophenyl)propyl] propanoate (1, IC(50) = 7.52 µg/mL or 28.38 µM; CC(50) = 35.77 µg/mL or 134.98 µM; SI = 4.75) and 2-[Hydroxy(2-nitrophenyl)hydroxyethyl] propanoate (9, IC(50) = 5.48 µg/mL or 20.52 µM; CC(50) = 29.81 µg/mL or 111.64c µM and, SI = 5.43) were the most effective and safe evaluated compounds.
Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Macrófagos/parasitología , Animales , Antiprotozoarios/química , Células Cultivadas , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Espectrofotometría InfrarrojaRESUMEN
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⻹ and 11.06µgmL⻹ respectively on L. amazonensis; 9.58µgmL⻹ and 14.34µgmL⻹ respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds.
Asunto(s)
Antiparasitarios/síntesis química , Antiparasitarios/farmacología , Tecnología Química Verde/métodos , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/farmacología , Leishmania/efectos de los fármacos , Acrilatos/química , Aldehídos/química , Antiparasitarios/química , Catálisis , Tecnología Química Verde/economía , Humanos , Hidrocarburos Aromáticos/química , Leishmaniasis/tratamiento farmacológico , Piperazinas/químicaRESUMEN
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.
Asunto(s)
Acrilonitrilo/análogos & derivados , Alcoholes Bencílicos/síntesis química , Alcoholes Bencílicos/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Acrilonitrilo/síntesis química , Acrilonitrilo/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Nitrilos , Trypanosoma cruzi/crecimiento & desarrolloRESUMEN
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.