Thiabendazole and Thiabendazole-Formic Acid Solvate: A Computational, Crystallographic, Spectroscopic and Thermal Study

Abstract

<jats:p>Thiabendazole (TBZ) is a substance which has been receiving multiple important applications in several domains, from medicine and pharmaceutical sciences, to agriculture and food industry. Here, a comprehensive multi-technique investigation on the molecular and crystal properties of TBZ is reported. In addition, a new solvate of the compound is described and characterized structurally, vibrationally and thermochemically for the first time. Density functional theory (DFT) calculations were used to investigate the conformational space of thiabendazole (TBZ), revealing the existence of two conformers, the most stable planar trans form and a double-degenerated-by-symmetry gauche form, which is ~30 kJ mol−1 higher in energy than the trans conformer. The intramolecular interactions playing the major roles in determining the structure of the TBZ molecule and its conformational preferences were characterized. The UV-visible and infrared spectra of the isolated molecule (most stable trans conformer) were also calculated, and their assignment undertaken. The information obtained for the isolated molecule provided a strong basis for the understanding of the intermolecular interactions and properties of the crystalline compound. In particular, the infrared spectrum for the isolated molecule was compared with that of crystalline TBZ and the differences between the two spectra were interpreted in terms of the major intermolecular interactions existing in the solid state. The analysis of the infrared spectral data was complemented with vibrational results of up-to-date fully-periodic DFT calculations and Raman spectroscopic studies. The thermal behavior of TBZ was also investigated using differential scanning calorimetry (DSC) and thermogravimetry. Furthermore, a new TBZ–formic acid solvate [2-(1,3-thiazol-4-yl)benzimidazolium formate formic acid solvate] was synthesized and its crystal structure determined by X-ray diffraction. The Hirshfeld method was used to explore the intermolecular interactions in the crystal of the new TBZ solvate, comparing them with those present in the neat TBZ crystal. Raman spectroscopy and DSC studies were also carried out on the solvate to further characterize this species and investigate its temperature-induced desolvation.</jats:p>

Solubility Measurement and Data Correlation of Thiabendazole in 12 Pure Organic Solvents from 283.15 to 323.15 K

“…Three thermodynamic and correlating models including modified Apelblat model, λ h model, and NRTL model were chosen to correlate the solubility of TBZ in 12 pure solvents from 283.15 to 323.15 K. The melting point of TBZ is about 573.85 K, and the enthalpy of fusion is about 35.19 kJ/mol based on published data. − …”

Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy

“…In the series, we also tested the antiproliferative activities against parasites of new benzimidazole salt formulations, recently licensed by some of us, which demonstrated improved bioavailability and solubility in vivo, in studies against secondary cystic echinococcosis using experimentally infected mice [24]. Remarkably, these patented salts were prepared to overcome the issues related to the poor aqueous solubility of the benzimidazole scaffold and the corresponding erratic bioavailability, as previously explored also by other authors through several strategies, including the inclusion in cyclodextrin complexes [25,26], the transformation into soluble prodrugs [27], the characterization and use of selected polymorphic forms and solvates [28], and the preparation of innovative formulations [29]. In addition to testing antiproliferative activities, we also predicted physico-chemical properties and putative molecular targets for our series of benzimidazoles, using an in silico approach, to further explore the polypharmacology of these compounds.…”