5-(2-Hydroxyethyl)-4-methylthiazole: Applications in Medicinal Chemistry and its Synthesis Method

General Description

5-(2-Hydroxyethyl)-4-methylthiazole shows promise in antimalarial drug development and as a core structure for cancer treatment. In antimalarial research, derivatives with alkylene linkers have demonstrated potent activity, though limited by toxicity. In cancer therapy, these compounds act as HDAC8-selective inhibitors, showing high potency and selectivity. The synthesis involves initial steps with alpha-acetyl-gamma-butyrolactone leading to the formation of 5-(2-Hydroxyethyl)-4-methylthiazole efficiently. 5-(2-Hydroxyethyl)-4-methylthiazole's versatility in targeting malaria and cancer showcases its potential in drug development, emphasizing the need to balance efficacy with safety in medicinal chemistry.

Figure 1. 5-(2-Hydroxyethyl)-4-methylthiazole

Applications in Medicinal Chemistry

Potential in Antimalarial Drug Development

5-(2-Hydroxyethyl)-4-methylthiazole has shown considerable promise as a core structure in the development of new antimalarial agents. Recent studies involving alkylenebisthiazolium salts, which are structurally related to 5-(2-Hydroxyethyl)-4-methylthiazole, have highlighted their potent antimalarial properties. These compounds, incorporating 5-(2-Hydroxyethyl)-4-methylthiazole derivatives with alkylene linkers that contain aryl rings, alkynes, or heteroatoms, have demonstrated improved physicochemical properties such as decreased lipophilicity and increased oral bioavailability. The efficacy of these derivatives has been underscored by their remarkable in vitro and in vivo antimalarial activities, with effective concentrations (EC50) less than 10 nM and effective doses (ED50) for intraperitoneal administration less than 0.7 mg/kg. However, the utility of these compounds is currently limited by their toxicity at higher dosages in animal models. The dual challenge in medicinal chemistry remains not only in harnessing the therapeutic potential of 5-(2-Hydroxyethyl)-4-methylthiazole derivatives but also in mitigating their toxicity. ¹

Role in HDAC8-Selective Inhibitors for Cancer Treatment

Beyond its antimalarial applications, 5-(2-Hydroxyethyl)-4-methylthiazole also holds potential in cancer therapy, particularly in the design of selective inhibitors for histone deacetylase 8 (HDAC8). In the search for effective HDAC8 inhibitors, 5-(2-Hydroxyethyl)-4-methylthiazole-based compounds have been explored due to their ability to interact specifically with the enzyme's active site. By incorporating a zinc-binding group that coordinates with the zinc ion at the HDAC8 active site and linking it via a triazole moiety to a capping structure, these inhibitors interact with key residues. This unique interaction not only enhances the potency but also the selectivity of these compounds against HDAC8, making them superior to other known inhibitors like PCI-34058. The importance of the 5-(2-Hydroxyethyl)-4-methylthiazole moiety in these molecules is evident in molecular modeling studies, which suggest that the positioning of this group within the enzyme's hydrophobic pocket is critical for achieving high potency and selectivity. As such, these inhibitors have shown significant potential in inhibiting the growth of T-cell lymphoma and neuroblastoma cells, suggesting a promising avenue for the development of cancer therapies leveraging the unique properties of 5-(2-Hydroxyethyl)-4-methylthiazole. ²

Synthesis Method

Initial Synthesis Steps

The method for synthesizing 5-(2-hydroxyethyl)-4-methylthiazole begins with the preparation of the initial compound, alpha-acetyl-gamma-butyrolactone. In a sealed reactor equipped with stirring and cooling devices, 100 weight parts of alpha-acetyl-gamma-butyrolactone are processed by slowly adding 80 weight parts of sulfonyl chloride while maintaining a temperature of 40-42°C for a duration of 1.5 to 2.5 hours. Following this reaction, the mixture is dried using calcium chloride (CaCl2), and then filtered to produce a refined alpha-acetyl-alpha-butyrolactone. This intermediary product is crucial for the subsequent chemical reactions that lead to the formation of 5-(2-hydroxyethyl)-4-methylthiazole. ³

Formation of 5-(2-Hydroxyethyl)-4-methylthiazole

Continuing the synthesis, the previously obtained alpha-acetyl-gamma-butyrolactone is reintroduced into a sealed reactor with a condensing reflux device. Here, either 77 weight parts of 5% sulfuric acid or 160 weight parts of 5% hydrochloric acid are added, and the mixture is heated to a boiling point and refluxed for 5-7 hours. The reaction mixture is then extracted using dichloromethane to collect the 3-chloro-3-acetyl propanol dichloromethane extraction liquid. In a subsequent step, this extraction liquid is combined with 100 weight parts of formamide in a reactor maintained between 28-32°C, to which 54 weight parts of phosphorus pentasulfide are slowly added over 1.5 to 2 hours. After additional stirring and extraction, the thioformamide dichloromethane solution is mixed with the previous 3-chloro-3-acetyl propanol solution and refluxed for 5-6 hours. The resulting mixture is cooled, the pH adjusted to 9-10 using 5% NaOH solution, and the oil phase separated and further extracted with dichloromethane. The final product, 5-(2-hydroxyethyl)-4-methylthiazole, is then obtained through vacuum distillation, highlighting the process's efficiency and cost-effectiveness by avoiding more complex steps like diazotization or hydrolysis typically required with thiourea-based methods. ³

Reference

1. Caldarelli SA, El Fangour S, Wein S, et al. New bis-thiazolium analogues as potential antimalarial agents: design, synthesis, and biological evaluation. J Med Chem. 2013; 56(2): 496-509.

2. Suzuki T, Ota Y, Ri M, et al. Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries. J Med Chem. 2012; 55(22): 9562-9575.

3. Zheng GF. Method for synthesizing 4-methyl-5-(2-hydroxyethyl)thiazole from alpha-acetyl-gamma-butyrolactone. 2014; Patent Number: CN103772313.