ABSTRACT
Novel water-soluble chitosan-isoniazid conjugates were synthesized by two methods: (1) the carbodiimide method using isoniazid (INH) and N-(2-carboxyethyl)chitosan (CEC), and (2) the reaction between INH and N-(3-chloro-2-hydroxypropyl)chitosan (CHPC). The solubility of the conjugates under physiological conditions was enhanced by phosphorylation. Method (1) is preferable in terms of obtaining conjugates with a high content of active substance; depending on reaction conditions, the degree of substitution in the INH-CEC conjugates varies from 0.08 to 0.39. Ultrasound treatment increased the reaction rate by a factor of 1.3-1.5, but caused partial degradation of the polymer. Consecutive modification led to a considerable decrease in polymer biodegradability in the following order: chitosan>CEC or CHPC>conjugate. In vitro screening of the antimicrobial activity against Mycobacterium tuberculosis H37Rv demonstrated a comparable or slightly higher minimum inhibitory concentration for conjugates than for INH itself (0.20, 0.25, and 1.05 µg INH/mL for INH, CEC-INH, and CHPC-INH, respectively). A slug mucosal irritation test employing Limax flavus revealed a lower toxicity for the conjugates than for INH by a factor of 3-4; the most noticeable toxicity decrease was observed for the conjugates obtained by method (1). Studies of acute toxicity in mice revealed a 3-4-fold increase in median lethal dose for the conjugates compared with INH (LD50 210, 850, and 650 mg INH/kg for INH, CEC-INH, and CHPC-INH, respectively).
Subject(s)
Antitubercular Agents/chemical synthesis , Chitosan/chemistry , Cytostatic Agents/chemical synthesis , Isoniazid/chemistry , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Antitubercular Agents/toxicity , Cytostatic Agents/chemistry , Cytostatic Agents/pharmacology , Cytostatic Agents/toxicity , Gastropoda/drug effects , Mice , Mycobacterium tuberculosis/drug effectsABSTRACT
We explore solvent dynamics effects in interfacial bond breaking electron transfer in terms of a multimode approach and make an attempt to interpret challenging recent experimental results (the nonmonotonous behavior of the rate constant of electroreduction of S2O8(2-) from mixed water-EG solutions when increasing the EG fraction; see Zagrebin, P.A. et al. J. Phys. Chem. B 2010, 114, 311). The exact expansion of the solvent correlation function (calculated using experimental dielectric spectra) in a series predicts the splitting of solvent coordinate in three independent modes characterized by different relaxation times. This makes it possible to construct a 5D free-energy surface along three solvent coordinates and one intramolecular degree of freedom describing first electron transfer at the reduction of a peroxodisulphate anion. Classical molecular dynamics simulations were performed to study the solvation of a peroxodisulphate anion (S2O8(2-)) in oxidized and reduced states in pure water and ethylene glycol (EG) as well as mixed H2O-EG solutions. The solvent reorganization energy of the first electron-transfer step at the reduction of S2O8(2-) was calculated for several compositions of the mixed solution. This quantity was found to be significantly asymmetric. (The reorganization energies of reduction and oxidation differ from each other.) The averaged reorganization energy slightly increases with increasing the EG content in solution. This finding clearly indicates that for the reaction under study the static solvent effect no longer competes with solvent dynamics. Brownian dynamics simulations were performed to calculate the electron-transfer rate constants as a function of the solvent composition. The results of the simulations explain the experimental data, at least qualitatively.
