RESUMEN
Quinazolines have long been known to exert varied pharmacologic activities that make them suitable for use in treating hypertension, viral infections, tumors, and malaria. Since 2014, we have synthesized approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines and evaluated their antimalarial activity via structure-activity relationship studies. Here, we summarize the results and report the discovery of 6,7-dimethoxy-N4-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazolin-4-amine (20, SSJ-717), which exhibits high antimalarial activity as a promising antimalarial drug lead.
Asunto(s)
Antimaláricos/farmacología , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Femenino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
BACKGROUND: Basic blue 3 is a promising anti-malarial lead compound based on the π-delocalized lipophilic cation hypothesis. Its derivatives with nitrogen atoms bonded to carbon atoms at the 3- and 7-positions on the phenoxazine ring were previously shown to exert potent antiprotozoal activity against Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei rhodesiense, and Leishmania donovani parasites in vitro. However, compounds with nitrogen modification at the 10-position on the phenoxazine ring were not evaluated. METHODS: Six acylphenoxazine derivatives (ITT-001 to 006) with nitrogen modification at the 10-position on the phenoxazine ring, which were synthesized from basic blue 3, were characterized and evaluated for anti-malarial activity in vitro with an automated haematology analyzer (XN-30) and light microscopy. Intensity of self-fluorescence was measured using a fluorometer. Localization of basic blue 3 was observed by fluorescence microscopy. Cytotoxicity was evaluated using human cell lines, HEK293T and HepG2 cells. Finally, anti-malarial activity was evaluated in a rodent malaria model. RESULTS: All the six derivatives showed anti-malarial efficacy even against chloroquine-, pyrimethamine-, and artemisinin-resistant field isolates similar to the sensitive strains and isolates in vitro. The efficacy of basic blue 3 was the strongest, followed by that of ITT-001 to 004 and 006, while that of ITT-005 was the weakest. Basic blue 3 showed strong self-fluorescence, whereas ITT derivatives had five- to tenfold lower intensity than that of basic blue 3, which was shown by fluorescence microscopy to be selectively accumulated in the plasmodial cytoplasm. In contrast, ITT-003, 004, and 006 exhibited the lowest cytotoxicity in HEK293T and HepG2 cells in vitro and the highest selectivity between anti-malarial activity and cytotoxicity. The in vivo anti-malarial assay indicated that oral administration of ITT-004 was the most effective against the rodent malaria parasite, Plasmodium berghei NK65 strain. CONCLUSIONS: The six ITT derivatives were effective against chloroquine- and pyrimethamine-resistant strains and artemisinin-resistant field isolates as well as the sensitive ones. Among them, ITT-004, which had high anti-malarial activity and low cytotoxicity in vitro and in vivo, is a promising anti-malarial lead compound.
Asunto(s)
Antimaláricos/farmacología , Oxazinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/toxicidad , Células HEK293 , Células Hep G2 , Humanos , Oxazinas/toxicidad , Pruebas de ToxicidadRESUMEN
A productive synthesis of benzo[a]phenoxazine derivative SSJ-183 (1), a promising lead for antimalarial agents, was developed using a one pot procedure. Furthermore, N-deethylated metabolite 3 and bis-N,N-deethylated metabolite 4 were synthesized by the application of the method. The metabolites 3 and 4 showed comparable and â¼2-fold increased activities against drug-sensitive and drug-resistant Plasmodium falciparum parasites.
Asunto(s)
Antimaláricos/farmacología , Oxazinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Piridinas/farmacología , Antimaláricos/síntesis química , Antimaláricos/metabolismo , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazinas/síntesis química , Oxazinas/metabolismo , Pruebas de Sensibilidad Parasitaria , Piridinas/síntesis química , Piridinas/metabolismo , Relación Estructura-ActividadRESUMEN
Several benzo[a]phenoxazine derivatives containing substituted N-aromatic groups are evaluated for their pH-dependent absorption and emission properties. Among the compounds exhibiting optical responses under near-neutral and subacid pH conditions, benzo[a]phenoxazine derivatives with an electron-withdrawing aromatic group attached to nitrogen of the imino group show potential application as near-infrared pH sensors. Three water-soluble pH probes based on benzo[a]phenoxazine with different pyridinium structures are designed and synthesized. Their reversible pH-dependent emissions in buffer solution containing 0.1% dimethyl sulfoxide (DMSO) locate in 625-850 nm with the fluorescent enhancement of 8.2-40.1 times, and their calculated pKa values are 2.7, 5.8, and 7.1, respectively. A composite probe containing the three benzo[a]phenoxazines shows a linear pH-emission relationship in the range of pH 1.9-8.0. Real-time detection of intracellular pH using an in vitro assay with HeLa cells is also reported.
Asunto(s)
Colorantes Fluorescentes/química , Rayos Infrarrojos , Oxazinas/química , Colorantes Fluorescentes/síntesis química , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Imagen Óptica , Fenómenos Ópticos , Oxazinas/síntesis químicaRESUMEN
An efficient approach to generate a fully functionalized cyclopenta[a]phenanthrene 34, the basic carbon framework of andrastin C (1c), is described. The present synthetic route features a stereoselective intramolecular Diels-Alder reaction of triene 12 and an intramolecular carbonyl ene reaction of 3-phenanthrenyl-2-(methoxymethoxy)propanal 31.
Asunto(s)
Androstadienos/síntesis química , Fenantrenos/química , Fenantrenos/síntesis química , Androstadienos/química , Estructura Molecular , EstereoisomerismoRESUMEN
A series of 5-phenyliminobenzo[a]phenoxazine derivatives were synthesized. The in vitro antiprotozoal activities were evaluated against Plasmodium falciparum K1, Trypanosoma cruzi, Leishmania donovani and Trypanosoma brucei rhodesiense. N,N-Diethyl-5-((4-methoxyphenyl)imino)-5H-benzo[a]phenoxazin-9-amine shows IC(50)=0.040 µmol L(-1) with a selective index of 1425 against Plasmodium falciparum K1.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Diseño de Fármacos , Oxazinas/síntesis química , Oxazinas/farmacología , Animales , Antimaláricos/toxicidad , Antiprotozoarios/química , Antiprotozoarios/toxicidad , Concentración 50 Inhibidora , Leishmania donovani/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria/epidemiología , Modelos Químicos , Estructura Molecular , Mioblastos , Oxazinas/química , Oxazinas/toxicidad , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Compuestos de Piridinio/química , Ratas , Relación Estructura-Actividad , Tiazoles/química , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/farmacología , Tripanocidas/toxicidad , Trypanosoma brucei rhodesiense/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacosRESUMEN
The benzo[a]phenoxazine derivative, SSJ-183 has shown excellent anti-malarial efficacy and safety. However, its mechanism of action is unclear. We investigated the effect of SSJ-183 on the rodent malarial parasite, Plasmodium berghei. We analyzed changes in protein expression in the erythrocytic cycle of P. berghei with or without 18 h of SSJ-183 treatment by two-dimensional gel electrophoresis. We confirmed results with matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight tandem mass spectrometry. After treatment, seven main proteins were significantly down-regulated, and two were up-regulated; results were reproduced in three independent tests. Some of these proteins were hypothetical parasite proteins or unnamed host products. However, three proteins were identified as a heat shock protein, a disulfide isomerase precursor, and berghepain-2 from P. berghei. All three showed reduced expression after SSJ-183 treatment. This suggested that SSJ-183 was a good anti-malarial drug candidate because it targeted parasite chaperone proteins.
Asunto(s)
Antimaláricos/química , Electroforesis en Gel Bidimensional/métodos , Oxazinas/farmacología , Plasmodium berghei/efectos de los fármacos , Proteoma/análisis , Piridinas/farmacología , Animales , Antimaláricos/farmacología , Proteínas de Choque Térmico/metabolismo , Ratones , Oxazinas/química , Plasmodium berghei/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Piridinas/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosRESUMEN
SSJ-127, a novel antimalarial rhodacyanine derivative, has shown potent antimalarial activity against chloroquine-resistant Plasmodium strains in vitro and subcutaneous administration of SSJ-127 results in a complete cure of a mouse malaria model. SSJ-127 was detected by fluorescence microscopy in the mouse malaria parasites Plasmodium berghei after exposure of infected red blood cells to the compound in vitro and in vivo. Selective accumulation of SSJ-127 in an organelle is observed in all blood stages of live malaria parasites. The organelle is clearly different from the mitochondrion and the nucleus in terms of morphology. The shape of the organelle changed during the asexual blood stages of the parasite. There was always a close association between the organelle and the mitochondrion. These results raised the possibility that SSJ-127 accumulates in an apicoplast of the malaria parasite and affects protozoan parasite-specific pathways.
Asunto(s)
Antimaláricos/química , Benzotiazoles/química , Oxazoles/química , Plasmodium berghei/efectos de los fármacos , Compuestos de Piridinio/química , Tiazoles/química , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacología , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Eritrocitos/parasitología , Ratones , Microscopía Fluorescente , Mitocondrias/metabolismo , Oxazoles/síntesis química , Oxazoles/farmacología , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/farmacología , Rodamina 123/metabolismo , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
In vivo antimalarial drug candidates screening test was carried out on a series of water-soluble 3,7-bis(dialkylamino)phenoxazin-5-ium derivatives. Among them, 3-(diethylamino)-7-(piperidin-1-yl)phenoxazin-5-ium chloride (SSJ-206) showing highest efficacy was chosen for further pharmcodynamics and pharmacokinetics study. It was supported from these data that the phenoxazinium salts, SSJ-206, would be one of hopeful candidates as an oral antimalarial drug.
Asunto(s)
Antimaláricos/farmacología , Antimaláricos/farmacocinética , Malaria/tratamiento farmacológico , Malaria/metabolismo , Oxazinas/farmacología , Oxazinas/farmacocinética , Animales , Antimaláricos/sangre , Femenino , Malaria/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Oxazinas/sangre , Oxazinas/química , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei/efectos de los fármacos , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
A multicomponent domino reaction involving three mechanistically distinct Tf2NH-catalyzed reactions was developed. The reaction cascade enables the assembly of a skewed 5/6/4 tricyclic motif with migration of the reactive site with the assistance of a catalyst. The tricyclic product was used to achieve the first total synthesis of cytotoxic paesslerin A by regioselective C-H insertion of the sulfonyl carbenoid and base-promoted olefin isomerization. Our results led to the revision of the originally proposed tricyclic structure of paesslerin A.
RESUMEN
3,7-Bis(dialkylamino)phenoxazinium salts were synthesized and evaluated for in vitro activities against Plasmodium falciparum, Trypanosoma cruzi, T. brucei rhodesiense, and Leishmania donovani. Notably, the compounds showed potent antiprotozoal activities, especially against P. falciparum and T. cruzi. The compounds with alkyl side chains less than three carbons in length possessed good activities with high selective indices.
Asunto(s)
Antiprotozoarios/síntesis química , Oxazinas/síntesis química , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Antimaláricos/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Cloroquina/farmacología , Resistencia a Medicamentos , Leishmania donovani/efectos de los fármacos , Oxazinas/química , Oxazinas/farmacología , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Pirimetamina/farmacología , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma brucei rhodesiense/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacosRESUMEN
A CO2-fixation reaction of 4-(benzylamino)-2-butynyl carbonates and benzoates, carried out in the presence of DBU, provides substituted 5-vinylideneoxazolidin-2-ones. The reaction has been successfully applied to the CO2-recycling process and fixation of atmospheric CO2.
Asunto(s)
Benzoatos/química , Dióxido de Carbono/química , Carbonatos/química , Oxazolidinonas/síntesis química , Urea/análogos & derivados , Estructura Molecular , Oxazolidinonas/química , Estereoisomerismo , Urea/químicaRESUMEN
A series of novel indoles were designed and their molecular modeling simulation study including fitting to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was examined as HCV NS3 protease inhibitor. Several compounds showed significant high simulation docking score and fit values. The designed compounds were synthesized and biologically evaluated in vitro using an NS3 protease binding assay, where compounds 10a-k showed significant inhibitory activity (> or =67% inhibition at 100 microg/mL). Of these, compounds 10c and 10f demonstrated potent HCV NS3 protease inhibitors with IC(50) values of 15 and 13 microM, respectively. Enantio-selective Michael addition of an indole derivative in the presence of catalytic amount of AlCl(3) and quinine at room temperature afforded the adduct 7e in excellent yield with 73% ee. The product was converted into 10l, which showed lower activity than the mixture of the corresponding diastereoisomers.
Asunto(s)
Diseño de Fármacos , Indoles/síntesis química , Indoles/farmacología , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitios de Unión/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Simulación por Computador , Diseño Asistido por Computadora , Indoles/química , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/química , Programas Informáticos , Estereoisomerismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/químicaRESUMEN
Phenoxazinium salts were found to display good antimalarial efficacy in vivo against Plasmodium berghei. Several compounds provided 100% parasitemia clearance at a dose of 20-30 mg kg-1x4 days (ip) and good survival effects without obvious acute toxicity. They also showed excellent potency by oral administration. A preliminary pharmacokinetic study revealed that the oral availability of 1a was excellent.
Asunto(s)
Antimaláricos/síntesis química , Oxazinas/síntesis química , Compuestos de Amonio Cuaternario/síntesis química , Administración Oral , Animales , Antimaláricos/química , Antimaláricos/farmacología , Resistencia a Medicamentos , Dosificación Letal Mediana , Malaria/tratamiento farmacológico , Ratones , Oxazinas/química , Oxazinas/farmacología , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacologíaRESUMEN
Several aza-fused rhodacyanines were synthesized and assessed for their in vitro and in vivo antimalarial activities against Plasmodium falciparum K1 and P. berghei. All synthetic compounds showed strong selective antimalarial in vitro activity. Class II azarhodacyanines, 3, consisting of four heterocyclic units, were found to display good parasitemia suppression and low acute toxicity in vivo. Among them, 3c appeared to be the most effective at a dose of 20-25 mg kg(-1) day(-1) (ip).
Asunto(s)
Antimaláricos/síntesis química , Compuestos Aza/síntesis química , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Compuestos de Piridinio/síntesis química , Tiazoles/síntesis química , Animales , Antimaláricos/farmacología , Antimaláricos/toxicidad , Compuestos Aza/farmacología , Compuestos Aza/toxicidad , Línea Celular , Resistencia a Medicamentos , Ratones , Plasmodium falciparum/efectos de los fármacos , Compuestos de Piridinio/farmacología , Compuestos de Piridinio/toxicidad , Tiazoles/farmacología , Tiazoles/toxicidadRESUMEN
A convergent total synthesis of (+)-mycalamide A is described. A Yb(OTf)3-TMSCl catalytic system is used to synthesize a trioxadecalin ring system, which contains the right segment of mycalamide A. In addition, a tetrahydropyran ring, which is the left segment, is constructed with use of a novel one-pot delta-lactonization protocol. Both segments are prepared from a common starting material, d-mannitol. These segments are then coupled and the functional groups are transformed to synthesize (+)-mycalamide A.
Asunto(s)
Manitol/química , Toxinas Marinas/síntesis química , Piranos/síntesis química , Animales , Catálisis , Toxinas Marinas/química , Estructura Molecular , Poríferos/química , Piranos/química , EstereoisomerismoRESUMEN
Cascade reactions are useful methods for the construction of polycyclic skeletons, which are important cores for biological activities. A variety of cascade reactions carried out under multiple reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions, have been investigated. Culmorin, pentalenene, pentalenic acid, deoxypentalenic acid, longiborneol, cedrandiol, 8,14-cedranoxide, atisirene, atisine, and estrane-type steroids were synthesized via the intramolecular double Michael reaction. Aza double Michael reaction was applied to the syntheses of tylophorine, epilupinine, tacamonine, and paroxetine. Furthermore, sequential Michael and aldol reactions were performed in both intramolecular and intermolecular manners, leading to the formation of polycyclic compounds fused to a four-membered ring. Synthesis of paesslerin A utilizing a multicomponent cascade reaction revealed an error in the proposed structure. Unique cascade reactions carried out under radical and transition metal-catalyzed reaction conditions were also investigated. With the combination of several cascade reactions, serofendic acids and methyl 7beta-hydroxykaurenoate, both of which have neuroprotective activity, were synthesized in a selective manner.
Asunto(s)
Productos Biológicos/biosíntesis , Química Farmacéutica , Compuestos Policíclicos/síntesis química , Sesquiterpenos/síntesis química , Alcaloides/síntesis química , Alcaloides/química , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Indolizinas/síntesis química , Indolizinas/química , Modelos Químicos , Óxidos/química , Fenantrenos/síntesis química , Fenantrenos/química , Compuestos Policíclicos/química , Sesquiterpenos/química , EstereoisomerismoRESUMEN
Total syntheses of serofendic acids A (1a) and B (1b) are described. The key strategic element of the approach involves the novel tin-free homoallyl-homoallyl radical rearrangement of 5 for the construction of bicyclo[2.2.2]octane ring system 4. In addition, the conversion of methyl atisirenoate 2 to serofendic acids A (1a) and B (1b) was achieved on the basis of the Michael reaction of sodium thiomethoxide.[reaction: see text]
Asunto(s)
Diterpenos/síntesis química , Fármacos Neuroprotectores/síntesis química , Catálisis , Diterpenos/química , Estructura Molecular , Fármacos Neuroprotectores/química , Estereoisomerismo , Estaño/químicaRESUMEN
The rhodacyanine dye MKT-077 (1), a potent antitumor agent, was found to possess strong in vitro activity against Plasmodium falciparum and a low cytotoxicity. Several new rhodacyanine dyes related to 1, containing a variety of linked heterocyclic moieties, were synthesized, and their antimalarial potencies were evaluated. The synthetic rhodacyanines were found to have EC(50) values against P. falciparum in vitro in the range of 4-300 nM. Several compounds in this series have remarkable selective toxicity profiles (>100).
Asunto(s)
Antimaláricos/síntesis química , Piridinas/síntesis química , Tiazoles/síntesis química , Animales , Antimaláricos/química , Antimaláricos/farmacología , Colorantes , Plasmodium falciparum/efectos de los fármacos , Piridinas/química , Piridinas/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
[reaction: see text] A cascade chirality transfer process has been achieved by the palladium-catalyzed reaction of substituted propargylic carbonates with phenols. The reaction proceeds in a highly enantiospecific manner to produce chiral cyclic carbonates, which supports the existence of the pi-propargylpalladium intermediate in the reaction mechanism. The (E)- and (Z)-selectivity of the products can be controlled by choice of the phosphine ligand.