RESUMEN
Catalytic amounts of 1,3-di(methyl)imidazole-2-ylidene, one of the simplest and most prototypical N-heterocyclic carbenes, can up-convert aldehydes into powerful stoichiometric sources of electrons (Super Electron Donors) for reductive transformations of iodoaryls (E red < -2 V). In particular, the hydroarylation of 1,1'-diarylethylenes, which may require high temperatures and inherently generate stoichiometric amounts of oxidized waste, was performed at room temperature, with the concomitant formation of esters as oxidized co-products.
RESUMEN
Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski's rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC50 = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC50 = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.
Asunto(s)
Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Animales , Enfermedad de Chagas/tratamiento farmacológico , Cricetinae , Cricetulus , Humanos , Pirroles , Relación Estructura-ActividadRESUMEN
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program.
Asunto(s)
Imidazoles/química , Imidazoles/farmacología , Piridinas/química , Piridinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Animales , Daño del ADN/efectos de los fármacos , Descubrimiento de Drogas , Células Hep G2 , Humanos , Imidazoles/metabolismo , Imidazoles/farmacocinética , Concentración 50 Inhibidora , Ratones , Pruebas de Sensibilidad Parasitaria , Piridinas/metabolismo , Piridinas/farmacocinética , Albúmina Sérica/metabolismo , Relación Estructura-Actividad , Tripanocidas/metabolismo , Tripanocidas/farmacocinéticaRESUMEN
In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC50 > 10 µM (vs 0.18 µM and 2.31 µM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 µM ≤ IC50 ≤ 2.18 µM vs IC50 = 2.31 µM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC50 > 10 µM).
Asunto(s)
Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Nitroimidazoles/farmacología , Oxazoles/farmacología , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Nitroimidazoles/síntesis química , Nitroimidazoles/química , Oxazoles/síntesis química , Oxazoles/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
The dichalcogenation of imidazoheterocycles led to the first functionalization of imidazo[1,2-a]pyrimidine cores on the C6-position. The methodology, involving iodine/dimethylsulfoxide oxidation of diaryldichalcogenides, started with C3-chalcogenation, followed by C6 selanylation, activated in acidic medium. This novel sequential dichalcogenation strategy proceeded efficiently with excellent regioselectivity and yields.
RESUMEN
By combining the structural features of dihydropyrimidinone and 1,2,3-triazole heterocycles, novel hybrid compounds were synthesized using a simple and convenient method. A series of novel mono and bis 1,2,3-triazole was synthesized via copper-catalyzed Huisgen azide-alkyne cycloadditions (CuAAC) under microwave irradiation. The newly synthesized compounds were evaluated for their antiviral activity against varicella-zoster virus (VZV). Compounds 6aa, 7ab, 6ba and 6da showed valuable antiviral activities, with EC50 values ranging from 3.6 to 11.3 µM against TK+ and TK- VZV and without measurable cell-growth inhibition.
Asunto(s)
Antivirales/farmacología , Herpesvirus Humano 3/efectos de los fármacos , Pirimidinonas/farmacología , Triazoles/farmacología , Antivirales/síntesis química , Antivirales/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirimidinonas/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
A one-pot regioselective bis-Suzuki-Miyaura or Suzuki-Miyaura/Sonogashira reaction on 2,4-dibromo-1-methyl-5-nitro-1H-imidazole under microwave heating was developed. This method is applicable to a wide range of (hetero)arylboronic acids and terminal alkynes. Additionally, this approach provides a simple and efficient way to synthesize 2,4-disubstituted 5-nitroimidazole derivatives with antibacterial and antiparasitic properties.
Asunto(s)
Antibacterianos , Antiparasitarios , Nitroimidazoles , Antibacterianos/síntesis química , Antibacterianos/química , Antiparasitarios/síntesis química , Antiparasitarios/química , Nitroimidazoles/síntesis química , Nitroimidazoles/químicaRESUMEN
Cross-coupling reactions between 2-methyl-2-propen-1-ol and various boronic acids are used to obtain aromatic-(2-methylallyl) derivatives. However, deboronation or isomerization side reactions may occur for several boronic acids. We describe herein the synthesis of original alkenes with good yields under mild reaction conditions that decrease these side reactions. The scope of this environmentally benign reaction is thereby extended to a wide variety of boronic acids. A mechanistic study was conducted and suggested a plausible catalytic cycle mechanism, pointing to the importance of the Lewis acidity of the boronic acid used.
Asunto(s)
Alquenos/química , Éteres Metílicos/química , Ácidos Borónicos/química , Catálisis , Propanoles/químicaRESUMEN
New diarylquinazolines displaying pharmaceutical potential were synthesized in high yields from 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline by using microwave-promoted regioselective Suzuki-Miyaura cross-coupling reactions.
Asunto(s)
Microondas , Quinazolinas/síntesis química , Catálisis , Fenómenos Químicos Orgánicos , Preparaciones Farmacéuticas/síntesis químicaRESUMEN
The multistep synthesis of new quinazoline-derived molecules and their in vitro antiplasmodial evaluation on the W2 chloroquino-resistant Plasmodium falciparum strain is described herein. These molecules have also been studied concerning their in vitro cytotoxicity toward two human cell lines (K652 and HepG2) in order to calculate their respective selectivity indexes (S.I.). Among the fourteen tested molecules, two exhibited both significant antiplasmodial activity (IC(50)=0.95 and 1.3 microM) and low toxicity (IC(50)>100 or 125 microM), compared with two reference drugs: chloroquine and doxycycline. The structure activity relationships establish that the molecular scaffold which exerts the best profile is the 6-nitro-2-(tosylmethyl)-N-(3-substituted-phenyl)-quinazolin-4-amine. The hit molecules were finally investigated regarding their potential action toward two other protozoa, Leishmania donovani and Toxoplasma gondii, showing that these molecules display a selective antiplasmodial activity.