RESUMO
Niclosamide, previously used as an anthelmintic drug is currently being repurposed for its anticancer activity. Niclosamide is a brick like biopharmaceutical classification system (BCS) class II drug with poor aqueous solubility and dissolution consequently leading to low bioavailability. By considering the physicochemical properties and geometry of niclosamide, inclusion complex with cyclodextrin was prepared by freeze drying method and characterized using FT-IR, DSC, PXRD, and 1HNMR. In silico molecular modeling study was performed to study the possible interactions between niclosamide and cyclodextrin. The anticancer activity of niclosamide formulation was evaluated through in vitro cell cytotoxicity study using various cancer cell lines. The potential of niclosamide complex for improvement of the bioavailability was evaluated in male BALB/c mice. In vitro cytotoxicity studies indicated significantly higher cytotoxicity at lower concentrations and the pharmacokinetic studies showed significant improvement in Cmax and Tmax of niclosamide from cyclodextrin complex in comparison to pure niclosamide alone.
Assuntos
Antineoplásicos/síntese química , Ciclodextrinas/síntese química , Composição de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Niclosamida/síntese química , Animais , Anticestoides/síntese química , Anticestoides/metabolismo , Antineoplásicos/metabolismo , Ciclodextrinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Niclosamida/metabolismoAssuntos
Anticestoides/farmacologia , Carbamatos/farmacologia , Cestoides/efeitos dos fármacos , Infecções por Cestoides/tratamento farmacológico , Moniezíase/tratamento farmacológico , Salicilanilidas/farmacologia , Administração Oral , Animais , Anticestoides/síntese química , Carbamatos/síntese química , Cestoides/crescimento & desenvolvimento , Infecções por Cestoides/parasitologia , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Fezes/parasitologia , Feminino , Dose Letal Mediana , Moniezíase/parasitologia , Contagem de Ovos de Parasitas , Salicilanilidas/síntese química , Ovinos , Carneiro DomésticoAssuntos
Anilidas/farmacologia , Anticestoides/farmacologia , Benzamidas/farmacologia , Himenolepíase/tratamento farmacológico , Hymenolepis/efeitos dos fármacos , Sulfonamidas/farmacologia , Anilidas/síntese química , Animais , Anticestoides/síntese química , Benzamidas/síntese química , Relação Dose-Resposta a Droga , Himenolepíase/parasitologia , Hymenolepis/crescimento & desenvolvimento , Camundongos , Niclosamida/farmacologia , Contagem de Ovos de Parasitas , Sulfonamidas/síntese químicaAssuntos
Anticestoides/farmacologia , Benzamidas/farmacologia , Himenolepíase/tratamento farmacológico , Hymenolepis/efeitos dos fármacos , Administração Oral , Animais , Anticestoides/síntese química , Benzamidas/síntese química , Relação Dose-Resposta a Droga , Himenolepíase/parasitologia , Hymenolepis/crescimento & desenvolvimento , Injeções Intraperitoneais , Dose Letal Mediana , Camundongos , Niclosamida/farmacologia , Contagem de Ovos de Parasitas , Relação Estrutura-AtividadeAssuntos
Anticestoides/farmacologia , Benzamidas/farmacologia , Himenolepíase/tratamento farmacológico , Hymenolepis nana/efeitos dos fármacos , Animais , Anticestoides/síntese química , Benzamidas/síntese química , Relação Dose-Resposta a Droga , Himenolepíase/parasitologia , Hymenolepis nana/fisiologia , CamundongosAssuntos
Anticestoides/administração & dosagem , Himenolepíase/tratamento farmacológico , Hymenolepis nana , Piperazinas/administração & dosagem , Quinolinas/administração & dosagem , Administração Oral , Animais , Anticestoides/síntese química , Anticestoides/química , Avaliação Pré-Clínica de Medicamentos , Camundongos , Piperazinas/síntese química , Piperazinas/química , Quinolinas/síntese química , Quinolinas/químicaRESUMO
The paper describes a procedure for manufacturing the new anthelminthic Tizanox. It shows it necessary to administer a larger dose of the drug than that of azinox (praziquantel) to treat experimental hymenolepiasis. However, the lower toxicity of Tizanox enhances its chemotherapeutical index.
Assuntos
Anticestoides/síntese química , Anticestoides/uso terapêutico , Himenolepíase/tratamento farmacológico , Isoquinolinas/síntese química , Isoquinolinas/uso terapêutico , Tiadiazinas/síntese química , Tiadiazinas/uso terapêutico , Animais , Anticestoides/análise , Anticestoides/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Isoquinolinas/análise , Isoquinolinas/toxicidade , Camundongos , Praziquantel/análogos & derivados , Praziquantel/uso terapêutico , Praziquantel/toxicidade , Espectrofotometria Infravermelho/estatística & dados numéricos , Tiadiazinas/análise , Tiadiazinas/toxicidadeRESUMO
A procedure was developed for the synthesis of the anthelminthic G-1460. The therapeutical doses (20 and 25 mg/kg) of the agent were defined for the treatment of monieziasis and gastrointestinal nematodes on an individual basis.
Assuntos
Anticestoides/síntese química , Antinematódeos/síntese química , Derivados de Benzeno/síntese química , Enteropatias Parasitárias/veterinária , Moniezíase/tratamento farmacológico , Infecções por Nematoides/veterinária , Doenças dos Ovinos/tratamento farmacológico , Animais , Anticestoides/uso terapêutico , Antinematódeos/uso terapêutico , Derivados de Benzeno/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Enteropatias Parasitárias/tratamento farmacológico , Infecções por Nematoides/tratamento farmacológico , Niclosamida/uso terapêutico , OvinosRESUMO
The paper outlines a procedure for manufacturing the anthelminthic Azinox (biltricide) using the new interfacial transfer catalyst benzyl-di-propyl (beta-hydroxyethyl)ammonium chloride. Azinox has been shown to be identical to biltricide (praziquantel) in its properties. Azinox tests on models of Opisthorchis felineus in golden hamsters and of Hymenolepis nana in albino outbred mice have indicated that the agent is not inferior to biltricide in its antitrematodal and anticestodal activities. Azinox displayed a high activity at the preimaginal stages of O. felineus and H. nana and at the larval stage of H.nana.
Assuntos
Anticestoides/síntese química , Antiplatelmínticos/síntese química , Praziquantel/análogos & derivados , Animais , Anticestoides/uso terapêutico , Anticestoides/toxicidade , Antiplatelmínticos/uso terapêutico , Antiplatelmínticos/toxicidade , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Feminino , Himenolepíase/tratamento farmacológico , Himenolepíase/parasitologia , Dose Letal Mediana , Masculino , Mesocricetus , Camundongos , Opistorquíase/tratamento farmacológico , Opistorquíase/parasitologia , Praziquantel/síntese química , Praziquantel/uso terapêutico , Praziquantel/toxicidadeRESUMO
The paper describes the synthesis of the new agent G-1697 which is 4-[(benzo-2,1,3-thiadiazolyl-4)amino]-5, 6,7,8-tetrahydrobenzothieno [2,3-d] pyrimidine and the results of testing its acute toxicity and antiparasitic activity on a model of Echinococcus multilocularis invasion at the larval stage in cotton rats. The maximum nonlethal dose of G-1697 was 4.0 g/kg for outbred mice of both sexes whose weight was 14-16 g. Adult cotton rats (males) received the agent with their feed in increasing daily doses for 3 weeks continuously on days 8 to 28 after infection. The daily dose of its active ingredient varied from 0.03 to 0.35 g/kg and averaged 0.12 g/kg (the mean total dose per session was 2.47 g/kg). The baseline weight of parasitic larvocysts (PL) per animal averaged 0.28 g at the baseline. In the treated and control rats sacrificed 34 days following infection, the mean mass of PL per animal was 0.95 and 7.51 g, respectively. In the cotton rats treated with G-1697, the suppressed growth index calculated by three parameters (moderate, maximum, and minimum mass of PL in the animals of the comparable groups after treatment with regard to the similar baseline variables) was 90.8, 91.0 and 92.7, respectively, versus the controls. Among all PL found in each animal, its death was approximately 70-90% in the treated rats.
Assuntos
Anticestoides/síntese química , Pirimidinas/síntese química , Tiadiazóis/síntese química , Animais , Anticestoides/uso terapêutico , Anticestoides/toxicidade , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Equinococose/tratamento farmacológico , Equinococose/parasitologia , Echinococcus/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Masculino , Camundongos , Pirimidinas/uso terapêutico , Pirimidinas/toxicidade , Sigmodontinae , Tiadiazóis/uso terapêutico , Tiadiazóis/toxicidade , Fatores de TempoRESUMO
A procedure has been developed to manufacture the anthelminthic Triclonate. The agent was tested for the treatment of sheep's natural monieziasis infection and it was found to have a high activity.
Assuntos
Anticestoides/síntese química , Anticestoides/uso terapêutico , Animais , Anticestoides/análise , Anticestoides/toxicidade , Avaliação Pré-Clínica de Medicamentos/veterinária , Camundongos , Moniezíase/tratamento farmacológico , Niclosamida/uso terapêutico , Ovinos , Doenças dos Ovinos/tratamento farmacológico , Espectrofotometria Infravermelho , Tecnologia FarmacêuticaAssuntos
Anticestoides/síntese química , Benzazepinas/síntese química , Himenolepíase/tratamento farmacológico , Isoquinolinas/síntese química , Animais , Anticestoides/uso terapêutico , Anticestoides/toxicidade , Benzazepinas/uso terapêutico , Benzazepinas/toxicidade , Avaliação Pré-Clínica de Medicamentos , Isoquinolinas/uso terapêutico , Isoquinolinas/toxicidade , Camundongos , Relação Estrutura-AtividadeRESUMO
The paper describes the synthesis of 6-[4-alkylpiperazinyl-1)phenylamino]-1,2,5-thiadiazolo[3,4-h ]quinolines where methyl (Drug G-1574) and ethyl (Drug G-1569) are alkyls. The two agents are as effective as mebendazole against the larval stage of Echinococcus multilocularis infection. Drug G-1574 has been demonstrated to ensure 100% recovery of spontaneously Hymenolepis nana-infected albino mice given doses 2.5-5 times lower than the effective dose of phenasal (niclosamide).
Assuntos
Anticestoides/síntese química , Anticestoides/uso terapêutico , Equinococose/tratamento farmacológico , Himenolepíase/tratamento farmacológico , Quinolinas/síntese química , Quinolinas/uso terapêutico , Animais , Anticestoides/toxicidade , Avaliação Pré-Clínica de Medicamentos , Equinococose/parasitologia , Feminino , Himenolepíase/parasitologia , Masculino , Mebendazol/uso terapêutico , Camundongos , Niclosamida/uso terapêutico , Quinolinas/toxicidade , SigmodontinaeRESUMO
The synthesis and the acute toxicity and anticestodal activity of l-alkyl-4-[-(heterylamino)phenyl]-piperazines are presented. These compounds were found to be able to suppress the growth of larvocysts of Echinococcus multilocularis in cotton rats when injected intraperitoneally in a single dose of 0.25 g/kg, close to capacity of mebendazole. The tested compounds were also highly effective against the adult stage of Hymenolepis nana. Experimentally infected mice given an oral single dose of 0.2-0.5 g/kg of the drug were radically cured.
Assuntos
Anticestoides/síntese química , Equinococose/tratamento farmacológico , Himenolepíase/tratamento farmacológico , Piperazinas/síntese química , Animais , Anticestoides/uso terapêutico , Anticestoides/toxicidade , Avaliação Pré-Clínica de Medicamentos , Feminino , Masculino , Camundongos , Piperazinas/uso terapêutico , Piperazinas/toxicidade , SigmodontinaeRESUMO
A series of 1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-alpha][2] benzazepine derivatives was prepared and the cestocidal activity of the compounds evaluated in an in vitro Taenia crassiceps screen. Many of these derivatives proved to be highly active, and 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b- octahydropyrazino[2,1-alpha][2]benzazepine, epsiprantel (BAN) (22), was selected for further development. The structure-activity relationships are discussed.
Assuntos
Anticestoides/síntese química , Benzazepinas/síntese química , Animais , Anticestoides/farmacologia , Anticestoides/uso terapêutico , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Fenômenos Químicos , Química , Cães , Isomerismo , Relação Estrutura-Atividade , Taenia/efeitos dos fármacos , Teníase/tratamento farmacológicoRESUMO
A series of substituted 1-hydroxy-2-naphthanilides 4--14 has been synthesized by treating 1-hydroxy-2-naphthoic acids 2 with substituted anilines 3. The nitronaphthanilides, on reduction and subsequent treatment with thiophosgene, gave the corresponding substituted 2-naphthanilide isothiocyanates 30--33. Substitution of the chlorine of 8 by various cyclic amines gave 3'-nitro-4'-substituted 1-hydroxy-2-naphthanilides 15--21. Various 3-aryl-4-oxo-2,3-dihydro-1,3-naphthoxazine-2-thiones 34-43 and 3 aryl-2,4-dioxo-2,3-dihydro-1,3-naphthoxazines 44--51 have been prepared by reacting the corresonding naphthanilides with thiophosgene and ethyl chloroformate, respectively. All the compounds were tested for their cestodicidal activity against Hymenolepis nana infection in rats; 30 was found to be the most active compound of the series, showing 100% clearance of infection at a single oral dose of 7.5 mg/kg.
Assuntos
Anilidas/síntese química , Anticestoides/síntese química , Naftalenos/síntese química , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Anticestoides/uso terapêutico , Cães , Himenolepíase/tratamento farmacológico , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Ratos , Relação Estrutura-Atividade , Teníase/tratamento farmacológicoRESUMO
2'-Chloro-1-hydroxy-2-naphthanilide-4'-isothiocyanate (4) has been synthesized as the structural analogue of yomesan (1) and was found to be active against experimental dwarf tapeworm Hymenolepis nana infection in rats at an oral dose of 7.5 mg/kg.
Assuntos
Anilidas/síntese química , Anticestoides , Anilidas/farmacologia , Animais , Anticestoides/síntese química , Hymenolepis/efeitos dos fármacos , Masculino , RatosRESUMO
Synthesis and properties of 2-cyclohexylcarbonyl-1,3,4,6,7,11b-hexahydro-2H-pyrazino [2,1-a] isoquinolin-4-one, a novel anthelmintic with excellent activity against all species of Schistosomes pathogenic to man and a wide range of cestodes, will be reported.
Assuntos
Anticestoides , Isoquinolinas , Esquistossomicidas , Anticestoides/síntese química , Isoquinolinas/síntese química , Esquistossomicidas/síntese químicaRESUMO
A number of 5-chloro-3'-nitro-4'-substituted salicylanilides (6--23) have been synthesized by treating 4',5-dichloro-3'-nitrosalicylanilide (5) with various sodium aryl oxides, alkoxides, or amines. These compounds have been tested against Hymenolepis nana infection in rats and have also been evaluated for their in vitro antimicrobial activity against various strains of bacteria and fungi. In the former test 17 was the most active cestodicidal agent showing activity at 30 mg/kg. In the antimicrobial screening, 22 inhibited the growth of all the bacteria and fungi used while 6 was active against the penicillin resistant Staphylococcus aureus at a minimum inhibitory concentration of 0.00609 microgram/mL.