RESUMEN
BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Fenotiazinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Ratones , Estructura Molecular , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Fenotiazinas/síntesis química , Fenotiazinas/químicaRESUMEN
Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.
Asunto(s)
Antituberculosos/farmacología , Compuestos de Organoselenio/farmacología , Fenotiazinas/farmacología , Animales , Antituberculosos/síntesis química , Antituberculosos/metabolismo , Antituberculosos/toxicidad , Chlorocebus aethiops , Sinergismo Farmacológico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Células HEK293 , Humanos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , NADH Deshidrogenasa/antagonistas & inhibidores , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/metabolismo , Compuestos de Organoselenio/toxicidad , Pruebas de Sensibilidad Parasitaria , Fenotiazinas/síntesis química , Fenotiazinas/metabolismo , Fenotiazinas/toxicidad , Unión Proteica , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Relación Estructura-Actividad , Células VeroRESUMEN
A series of 19 derivatives of 2,7-diazaphenothiazine was synthesized and evaluated for their antioxidant activity bearing in mind the structural similarity with "classical" phenothiazines several of which are considered powerful antioxidants. Among the new derivatives that inhibited in vitro Fe(2+)/ascorbate-induced lipid peroxidation of rat liver microsomal membranes, several exhibited significant antioxidant activity with IC(50 )values in the range of 64-125 microM. Although N-substitution led to a variable degree of antioxidant activity, the latter appears to correlate with the lipophilicity (expressed as clogP values) of the substituted derivatives. Reduced lipophilicity may also explain the relatively lower protection offered by these derivatives against lipid peroxidation when compared to their "classical" phenothiazine counterparts. Thus, modification of the phenothiazine structure by a substitution of two benzene rings with pyridine rings to form this new type of azaphenothiazines does not enhance antioxidant activity, although it retains it.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Fenotiazinas/síntesis química , Fenotiazinas/farmacología , Animales , Antioxidantes/química , Ácido Ascórbico/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Compuestos Férricos/farmacología , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Estructura Molecular , Fenotiazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A biphasic gastroretentive drug delivery system of fenoverine was developed to maintain constant plasma concentration. The delivery system consisted of a loading-dose tablet and a floating multiple matrix tablet prepared by the direct compression process. The drug release from biphasic GRDDS in 0.1 mol L(-1) HCl and SGF (enzyme free) was sustained over 12 h with buoyant properties. Stability studies showed no significant change in dissolution profiles (f2 value > 50). Based on the release kinetics, it can be concluded that the floating multiple matrix tablet containing HPMC was a particularly suitable gastroretentive drug delivery system with a zero-order release profile.
Asunto(s)
Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos/métodos , Fármacos Gastrointestinales/administración & dosificación , Fenotiazinas/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Fármacos Gastrointestinales/síntesis química , Fármacos Gastrointestinales/farmacocinética , Fenotiazinas/síntesis química , Fenotiazinas/farmacocinética , ComprimidosRESUMEN
Synthesis and antibacterial screening of a homologous series of 3-dialkylaminophenothiazinium-7-norfloxacin conjugates was carried out alongside a corresponding series of symmetrical methylene blue derivatives. The norfloxacin conjugates maintained typical methylene blue derivative photoproperties, such as long wavelength absorption, but produced no measurable singlet oxygen in the standard assay and provided no significant increase in the magnitude of photoantibacterial action, this being similar to the methylene blue homologues, although both the conjugates and homologues were considerably more active than methylene blue itself both against Staphylococcus aureus and Escherichia coli. DNA binding via intercalation was considerably greater for the series of norfloxacin conjugates than for the methylene blue homologues.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Fluoroquinolonas/química , Fluoroquinolonas/farmacología , Fenotiazinas/química , Fenotiazinas/farmacología , Antibacterianos/síntesis química , Evaluación Preclínica de Medicamentos , Escherichia coli/efectos de los fármacos , Fluoroquinolonas/síntesis química , Humanos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Estructura Molecular , Fenotiazinas/síntesis química , Staphylococcus aureus/efectos de los fármacosRESUMEN
Methods of synthesis are described for 10H-pyridazino[4,5-b] [1,4]benzothiazine with alkylamine groups at the 1 and 4 position, triazole derivatives of the same heterocycle containing a pentadecanoic chain and derivatives with dialkylaminoalkyl groups at N-10. The results of pharmacological and microbiological examination are reported.