RESUMEN
A 7%w/w ectoine formula, from natural source, is formulated to reduce melanomagenesis, enhance penetration by 3D printed microneedles (MNs), with specified length, diameter and tip to ensure painless effect. Ectoine gel formulations were prepared using Carbopol 940 and Pluronic (F127). The effect of the polymers on pH, viscosity, spreadability, and the in vitro, ex vivo release profiles was obtained. The physiochemical investigation showed uniform gel formulations. The formulations' in vitro and ex vivo drug release displayed a controllable drug release pattern, reaching 63.7-96% and 73-94.7% after 24 h. The permeation study of the in vitro and ex vivo release revealed that the drug release from gels followed diffusion mechanism. The selected formula was used, 3D printed MN array was applied to treat melanoma. Male rats were used for induction of melanoma using 0.5% of 7,12-dimethylbenz[a]anthracene three times weekly for 12 weeks, histopathology was applied to ensure development of carcinoma then rats were treated using the selected formula. Following treatment for continuous 6 weeks, histopathology showed a change in anatomy of skin, which started to return to its normal structure. The anti-melanogenesis activity of optimum formula of ectoine gel, enhanced by 3D printed MN, was found to be effective in reducing the severity of skin cancer reinforcing the efficacy of the promising treatment.
Asunto(s)
Melanoma , Absorción Cutánea , Ratas , Masculino , Animales , Administración Cutánea , Piel/metabolismo , Geles/química , Poloxámero/química , Melanoma/tratamiento farmacológico , Impresión TridimensionalRESUMEN
The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 µg/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2× the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 h, suggesting a once-daily dosing regimen.
Asunto(s)
Antibacterianos/farmacología , Carbapenémicos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Pirazoles/farmacología , Tiazoles/farmacología , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Biopelículas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
A series of second-generation analogues for 2-(1-(2-(4-butylphenyl)-4-methylthiazol-5-yl)ethylidene)aminoguanidine (1) have been synthesized and tested against methicillin-resistant Staphylococcus aureus (MRSA). The compounds were designed with the objective of improving pharmacokinetic properties. This main aim has been accomplished by replacing the rapidly hydrolyzable Schiff-base moiety of first-generation members with a cyclic, unhydrolyzable pyrimidine ring. The hydrazide-containing analogue 17 was identified as the most potent analogue constructed thus far. The corresponding amine 8 was 8 times less active. Finally, incorporating the nitrogenous side chain within an aromatic system completely abolished the antibacterial character. Replacement of the n-butyl group with cyclic bioisosteres revealed cyclohexenyl analogue 29, which showed significant improvement in in vitro anti-MRSA potency. Increasing or decreasing the ring size deteriorated the antibacterial activity. Compound 17 demonstrated a superior in vitro and in vivo pharmacokinetic profile, providing compelling evidence that this particular analogue is a good drug candidate worthy of further analysis.