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1. Introduction

Nitrogen-containing heterocyclic compounds play an important role in the drug discovery process, as approximately 75% of FDA (Food and Drug Administration)-approved small-molecule drugs contain one or more nitrogen-based heterocycles [1]. Thiazole, or 1,3-thiazole, belongs to the class of azoles and contains one sulfur atom and one nitrogen atom at positions 1 and 3. Its diverse biological activity is reflected in a large number of clinically approved thiazole-containing compounds with an extensive range of pharmacological activities. Most of these compounds are 2,4-disubstituted thiazole derivatives, and only a few are 2,5-disubstituted or 2,4,5-trisubstituted thiazoles [2].

Several drugs such as sulfathiazole; aztreonam; numerous cephems (ceftaroline, cefotiam, ceftibuten, cefixime, ceftriaxone, cefotaxime, ceftazidime, cefmenoxime, ceftizoxime, cefepime, cefdinir) with antibacterial effects; pramipexole with antiparkinsonian activity; edoxaban with antithrombotic effects; isavuconazole with antifungal effects; famotidine and nizatidine with antiulcer activity; meloxicam with anti-inflammatory effects; tiazofurin, dabrafenib, dasatinib, ixabepilone, and epothilone with antitumor effects; mirabegron as a β3-adrenergic receptor agonist; nitazoxanide and thiabendazole with antiparasitic effects; and febuxostat with antigout activity contain one thiazole moiety in the structure (Figure 1) [2–4].

Figure 1. Clinical drugs bearing one thiazole ring.

Compounds bearing two thiazole rings, such as the antitumor drug bleomycin, the antiretroviral agent ritonavir, the pharmacokinetic enhancer for HIV drugs cobicistat, and the antibacterial agent cefditoren, have been authorized on the pharmaceutical market (Figure 2) [2,5].

Figure 2. Clinical drugs bearing two thiazole rings.

The high medicinal significance of this scaffold has attracted considerable attention from many researchers and encouraged the design and synthesis of numerous thiazole- and bisthiazole-containing compounds with diverse pharmacological activities, such as antibacterial [6], antifungal [7], antiprotozoal [8], antiviral [9,10], anticancer [11], anti-inflammatory [12–16], antioxidant [17], analgesic [18], anticonvulsant [19], antidiabetic [20], and antihypertensive [21] activities. Furthermore, thiazole compounds exhibiting a promising biological potential for the treatment of Alzheimer’s disease [22,23] and metabolic syndrome [24] have been reported in the scientific literature.

2. Chemistry of Thiazole

Free thiazole is a pale-yellow flammable liquid, with a pyridine-like odor and a boiling point in the range of 116-118 °C. It has an aromatic character, due to the delocalization of a lone pair of electrons from the sulfur atom, resulting in a 6π-electron system. Also, its high aromaticity is highlighted by proton nuclear magnetic resonance, the chemical shift values of each proton within the thiazole ring being situated between 7.27 and 8.77 ppm. The resonance structures of thiazole are illustrated in Figure 3 [25,26].

Figure 3. The resonance structures of thiazole.

The calculated π-electron density revealed that the electrophilic substitution takes place preferentially at the C-5 position, followed by the C4-position (Figure 4). The nucleophilic substitution occurs at the C-2 position [27].

Figure 4. Calculated π-electron density of thiazole.

The acidity given by the presence of the three hydrogen atoms decreases in the order H2 >> H5 > H4 [4].

3. Synthesis of Thiazole and Bisthiazole Derivatives

Hantzsch synthesis is the oldest and most widely known method for the synthesis of a thiazole ring. The method consists of a cyclization reaction between alpha-halocarbonyl compounds and various reactants containing the N-C-S fragment. Examples of such compounds include thiourea, thioamides, thiosemicarbazides, and thiosemicarbazones [28].

The condensation of thioamides with various alpha-halocarbonyl compounds is commonly used. Many thiazoles with alkyl, aryl, or heteroaryl substituents at position 2, 4, or 5 can be obtained through this reaction. The reaction mechanism consists of the nucleophilic attack of the thioamide sulfur atom on the alpha carbon of the alpha-halocarbonyl, with the formation of an intermediate compound, which by subsequent dehydration leads to the corresponding thiazole (Scheme 1).

By the reaction of thiourea with alpha-halocarbonyl compounds, monosubstituted or disubstituted 2-aminothiazoles can be obtained, while by using other compounds containing thioamide moieties, such as thiosemicarbazides and thiosemicarbazones, 2-hydrazinothiazole and thiazol-2-yl-hydrazone derivatives can be synthesized in good yields. The condensation reactions occur through imino thioether and hydroxythiazoline intermediates, which are sometimes stable and isolable. The alpha-halocarbonyl component may be represented by alpha-haloketones and alpha-haloesters [29,30].

Scheme 1. Reaction mechanism of Hantzsch thiazole synthesis.

Moreover, thiazoles can be obtained through Gabriel synthesis [25,31], Cook-Heilbron synthesis [29,30], or by reacting various compounds such as isocyanide derivatives and carboxymethyl dithioates [32], propargyl bromides and thiourea derivatives [33], oximes, anhydrides and potassium thiocyanate [34], aldehydes, amines and element sulfur [35], vinyl azides and potassium thiocyanate [36].

Numerous heterocyclic compounds possessing the thiazole ring have been obtained in good to excellent yields using microwave irradiation [37,38]. Compared to conventional methods, microwave-assisted synthesis has several advantages, being an environmentally friendly and cost-effective tool, that leads to improved yields in short reaction times [39].

The synthesis of symmetrical 2,2`-bisthiazole compounds occurs most frequently by condensation of dithiooxamide with α-bromoketones at a ratio of 1:2, in ethanol at reflux [40-42].

The synthesis of symmetrical 4,4`-bisthiazole derivatives is most often performed by a condensation reaction of thioamides with 1,4-dibromo-2,3-butanedione, in a molar ratio of 2:1, in ethanol at reflux [43,44].

Several methods for the synthesis of 5,5`-bisthiazole compounds, starting from halogenated derivatives by transition metal-catalyzed arylation or cross-coupling reactions, have been reported in the literature [45,46].

Numerous protocols for the synthesis of thiazolyl-linker-thiazole compounds have been reported in the literature, most of them being based on the Hantzsch condensation reaction. The reaction can occur in a single step, when the two thiazole rings are formed simultaneously, using starting compounds such as bis-thiosemicarbazones, 2,5-dithiobiurea, bis-hydrazonoyl halides or dihalo diketones, or in two steps respectively, when the two thiazole rings are formed successively [47–52].

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