Characterization and structural analysis of the potent antiparasitic and antiviral agent tizoxanide

Tizoxanide [2-(hydroxy)-N-(5-nitro-2-thiazolyl)benzamide, TIZ] is a new potent anti-infective agent which may enhance current therapies for leishmaniasis, Chagas disease and viral hepatitis. The aim of this study was to identify the conformational preferences that may be related to the biological activity of TIZ by resolving its crystal structure and characterizing various physicochemical properties, including its experimental vibrational and 13C nuclear magnetic resonance properties, behavior on heating and solubility in several solvents at 25 °C. TIZ crystallizes from dimethylformamide as the carboxamide tautomer in the triclinic system, space group P(−1) (No. 2) with the following unit cell parameters at 173(2) K: a = 5.4110(3) Å, b = 7.3315(6) Å, c = 13.5293(9) Å, α = 97.528(3), β = 95.390(4), γ = 97.316(5), V = 524.41(6) Å3, Z = 2, Dc = 1.680 g/cm3, R1 = 0.0482 and wR2 = 0.0911 for 2374 reflections. This modification of TIZ has a ‘graphitic’ structure and is composed of tightly packed layers of extensively hydrogen-bonded molecules. The various spectroscopic data [Diffuse Fourier transform infrared (DRIFT) and FT-Raman, recorded in the range 3600–500 and 4000–200 cm−1 respectively, and solid-state 13C NMR] were consistent with the structure determined by X-ray crystallography. From DSC, TG and thermomicroscopy, it was concluded that TIZ is thermally stable as a solid and that melting is not an isolated event from the one-step thermal decomposition that it undergoes above 270 °C. This modification of TIZ is practically insoluble in water and slightly soluble in polar aprotic solvents such as dimethylsulfoxide, dimethylformamide and dioxane.

Graphical abstractTizoxanide [2-(Hydroxy)-N-(5-nitro-thiazolyl)benzamide, TIZ],a new potent anti-infective agent, has been structurally characterized by X-ray analysis, solid-state NMR, DRIFT, FTRaman and Thermal Analysis. This modification of TIZ has relatively high thermal stability as a solid and a ‘graphitic’ structure, and is composed of tightly packed layers of extensively hydrogen bonded molecules.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The crystal structure of unsolvated tizoxanide (TIZ) was resolved. ► This modification of TIZ has a ‘graphitic’ structure. ► The various spectroscopic data were consistent with the resolved structure. ► The behavior on heating of TIZ was studied by DSC, TG and HSM. ► TIZ decomposes above 270 °C and no isolated melting event was detected.