Preclinical pharmacokinetic study of a new thiazolyl hydrazone derivative with antifungal activity in mice plasma by LC-MS/MS

Discovery of Lead 2-Thiazolylhydrazones with Broad-Spectrum and Potent Antifungal Activity

“…60 We selected reagents available for purchase on Sigma-Aldrich that could be used to synthesize 2-thiazolylhydrazones: nonaromatic aldehyde/ketones and primary and secondary alcohols that could be oxidized to the corresponding carbonylic compound and α-haloketones. Reagents were then filtered based on the following criteria: (i) reagents must not have a molecular weight higher than 350 Da and without lowabundant isotopes ( 2 H, 13 C, 14 C, 17 O, 18 O); (ii) only aldehydes and ketones without hydrazines, primary and secondary amines, and epoxides in their structures, totalizing 802 carbonylic molecules; (iii) only alcohols without halides or amines in their structures, totalizing 160 alcohols that generated additional 160 carbonylic molecules; and (iv) only α-haloketones without other types of alkyl and acyl halides, esters, thioesters, amides, and primary and secondary aliphatic amines (the absence of these moieties aims to avoid undesirable reactions), totalizing 191 molecules. At the end, 145,162 unique molecules were generated after combining the reagents on possible in silico reactions.…”

“…The structural characteristics of this class of compounds allow the use of molecular modification strategies of groups linked to the thiazolylhydrazone moiety (Figure ), indicated as a pharmacophore by studies of the structure–activity relationship. These changes contribute to the modulation of physicochemical parameters related to the solubility and biological activity of these molecules. − …”

“…Thiazolylhydrazones with potent in vitro and in vivo antifungal activity have been described by our research group (Figure ) with a low cytotoxicity profile on cell-based assays. − However, the most active compounds in this class have low water solubility, which limits their potential therapeutic use. For example, a preclinical pharmacokinetic study of 2-thiazolylhydrazone RN104 demonstrated very low bioavailability when administered per os which may be a result of the high lipophilic profile of the compound (log P = 5.42) . Thus, to improve the physicochemical characteristics related to the water solubility of 2-thiazolylhydrazones, a new series of molecules were designed from the introduction of ionizable polar groups and/or substitution of hydrophobic substituents by others with better physicochemical properties to increase the oral bioavailability while maintaining antifungal activity and low cytotoxicity of these compounds.…”

Stability Indicating Method for a Thiazolylhydrazone Derivative with Antifungal Activity and Experimental/Theoretical Elucidation of Its Degradation Products

“…RN104 at dose of 5 mg kg -1 significantly prolonged survival of infected larvae and at the dose of 10 mg kg -1 per day over 15 days was as effective as fluconazole in prolonging the survival of mice infected with C. gattii and C. albicans. 5 In a preclinical pharmacokinetic study in mice, 6 RN104 was rapidly absorbed, reaching the maximum plasmatic concentration 20 min after administration. The bioavailability of per os route was approximately 40% of the intraperitoneal route.…”