**3. Thiazoles**

#### **3.1 Structure**

Thiazoles are five-membered aromatic heterocycles belonging to the azole group. While azoles are generally characterized by the presence of a nitrogen atom, the thiazole ring features the N in a 1,3-linkage with sulfur. The sulfur atom bears a lone pair of electrons which are delocalized throughout the ring, while C2 bears an acidic proton allowing for a range of reactions to occur in this position (**Figure 11**) [14].

#### **3.2 Biological applications of Thiazoles**

Thiazoles are noted for their utility in medicinal chemistry as an active and often potent pharmacophore [15] and are investigated for their therapeutical potential. Thiazoles are found in biologically relevant compounds such as the natural product Thiamin or Vitamin B1 and the first effective antibiotic drug series, Penicillin (**Figure 12**).

Additionally, there has been a growing interest in the synthesis of thiazole-containing compounds for applications as photosensitizers, sensors, catalysts, pigments, and more [16].

Certain biological applications of thiazoles were first identified in 1887 by Hantzsch and Weber. Since this discovery, thiazoles are a notable moiety present in several modern compounds of interest for their antitubercular [17], antidiabetic [18], antimalarial [19], antibacterial [19–31], antiviral [26, 32–34], antifungal [22, 24–27, 29, 30, 33, 34], antioxidant [35], anti-inflammatory [30, 35], anti-cancer [36, 37], and anti-proliferative [27, 38–40], activities.

**Figure 13** represents a few examples of approved drugs that contain a thiazole ring. Epothilones are a class of anti-neoplastic agents first identified in 1995,

**Figure 11.** *Resonance of unsubstituted 1,3-thiazole.* *Synthetic Strategies and Biological Activities of 1,5-Disubstituted Pyrazoles and 2,5-Disubstituted… DOI: http://dx.doi.org/10.5772/intechopen.108923*

**Figure 12.** *Biologically relevant thiazole derivatives.*

#### **Figure 13.**

*Approved drugs bearing thiazole moieties.*

which act by stabilizing microtubules and inducing apoptosis [41, 42]. Ritonavir was discovered in 1998 as a potent and effective HIV protease inhibitor [43] and today, is used in combination with other antiretroviral agents in the treatment of HIV infection. More recently, it has been used in combination therapy with lopinavir to treat severe Covid-19 [44, 45]. The prodrug Cefpodoxime Proxetil was identified in 1993 as a safe and effective broad-spectrum antibiotic [46–48]. The thiazole moiety is unquestionably a vital functionality in the structure of many drugs.

### **3.3 Conventional synthesis of 2, 4, 5-Thiazoles**

The synthesis of thiazoles has been broadly described in literature over the years. The main methods used to prepare thiazoles are the Hantzsch, Cook-Heilbron and Gabriel's syntheses as shown in **Figure 14** [16].

Hantzsch's synthesis of thiazole rings was first published in 1887 by Hantzsch and Weber [49]. Hantzsch's synthesis involves the condensation and aromatization of α-haloketones with nucleophilic thioamides containing the N-C-S fragment, where cyclization yields the thiazole moiety [16].

**Figure 14.**

*General synthetic scheme of 2,4,5-subsituted thiazoles by a) Hantzsch's synthesis B) Cook-Heilbron's synthesis and C) Gabriel's synthesis [16].*

The Cook-Heilbron reaction involves the interaction of aminonitrile derivatives with esters or various reactants containing a X-C-S fragment (such as dithioacids, carbon disulfide) under mild conditions to yield aminothiazoles [16, 50–53]. This synthesis generally introduces different moieties to the 2-position of 4- or 5-aminothiazoles.

Gabriel's synthesis was introduced in 1910 and describes the reaction between acylaminocarbonyls and phosphoruspentasulfide (such as Lawesson's reagent) to yield a thiazole ring with phenyl and alkyl substitutions in the 2- and 5-positions [16, 54].

#### **3.4 Recent synthetic routes towards 2,4,5-substituted thiazoles**

#### *3.4.1 Hantzsch's synthesis from Thioamide andα-Halocarbonyls*

**Figure 15** describes the synthesis of MSI-1 (3-(5-isopropyl-4-(4-methylpyridin-3-yl) thiazol-2-yl) benzamide), a natural product monomer which acts as a SREBP-1 inhibitor in the treatment for lung squamous cell carcinoma (LUSC). It also enhances the sensitivity of these cancer cells to antitumor agents. Compound **40** was brominated to obtain **41** and in a parallel reaction, the thioamide derivative **43** was generated from **42**. Subsequently, MSI-1 was obtained from the cyclocondensation reaction between α -halocarbonyl **41** and thioamide derivative **43** [55].

The reaction mechanism may proceed as shown in **Figure 16** as described by Hantzsch A and Weber [49], where bromine of **45** acts as a leaving group of allowing the coupling of sulfur of **46** to the α-position of the carbonyl. Following a series of several proton transfers, cyclization occurs via the nucleophilic attack of nitrogen to

**Figure 15.** *Hantszch's reaction between α-halocarbonyl* **41** *and thioamide* **43** *[55].* *Synthetic Strategies and Biological Activities of 1,5-Disubstituted Pyrazoles and 2,5-Disubstituted… DOI: http://dx.doi.org/10.5772/intechopen.108923*

**Figure 16.** *Plausible mechanism of Hantzsch's reaction [49].*

the electron-deficient carbonyl carbon and the desired product **47** is obtained after elimination of water [55].

Molecular docking studies show that MSI-1 enters the hydrophobic pocket of SREBP-1, binding through π-π conjugation. The complex is stabilized by further π-π interactions with three amino acid residues PHE271, TYR335, and PHE349. MSI-1 was shown to impedes the activation of SREBP-1 by inhibiting downstream genes of SREBP-1 associated to lipid metabolism in a dose dependent manner. Additionally, MSI-1 inhibits the Warburg Effect of cancerous and malignant cells and the Epithelial-Mesenchymal Transition process (indicative of chemo-resistance) in LUSC cell line NCI-H226. This effect was demonstrated by a decrease in glucose uptake and lactate production, as well as a reduction in ATP production and LDH activation [55].

#### *3.4.2 Hantzsch's synthesis from Thiourea andα-Halocarbonyls*

Wang *et al* recently reported the synthesis of thiazole-naphthalene hybrids and their antiproliferative activities as tubulin polymerization inhibitors from thiourea and α-halocarbonyls (**Figure 17**) [56]. The condensation of 1-methoxynaphtalene **48** with phenylacetic acid **49** in presence of trifluoroacetic anhydride (TFAA) in trifluoroacetic acid (TFA) yielded deoxybenzoin **50**. Compound **50** was then treated with pyridinium tribromide (PyBr3) in CH2Cl2 to brominate the α-position of the carbonyl. Finally, under reflux in ethanol, the cyclocondensation reaction of **51** and thiourea **52** produced desired compound **53**. Three thiazole-naphthalene derivatives were prepared with this protocol. Moreover, fourteen compounds were generated by introducing substitutions to the amine in the presence of acid anhydride [56].

Compound **53** showed potent antiproliferative activity on the human breast cancer (MCF-7) and human lung adenocarcinoma (A549) cell lines when compared to standard treatments (cisplatin, 5-fluorouracil, tamoxifen, and CA-4). They determined that the 4-ethoxyphenyl substitution was more favorable than 4-methoxyphenyl. Additionally, replacement with 2-bromo-3,4,5-trimethoxyphenyl reduced the antiproliferative activity [56]. Compound **53** exhibited low toxicity in human normal cell line (IC50 = 16.37 ± 4.61 μM). Its *in vitro* tubulin polymerization inhibitory activity of was investigated and revealed that the compound acts as a tubulin destabilizing agent with an IC50 of 3.3 μM (compared to reference colchicine IC50 of 9.1 μM). Furthermore, it was demonstrated that compound **53** leads to cell cycle arrest at the metaphase in a dose-dependent manner, and an Annexin V-FITC/PI assay showed

**Figure 17.** *Hantszch reaction between α-halocarbonyl* **51** *and thiourea* **52** *[56].*

that it can effectively induce apoptosis in MCF-7 cells. Molecular docking studies revealed that **53** can bind with tubulin by adopting an "L-shaped" conformation. The naphthalene moiety can accommodate in the hydrophobic pocket of the protein, and it binds to the colchicine site of tubulin [56].

### *3.4.3 Holzapfel: Meyers: Nicolaou modification of Hantzsch's synthesis*

The Holzapfel-Meyers-Nicolaou modification is based on the Hantzsch reaction between thioamide and an α-halocarbonyl, however, it involves the generation of a hydroxythiazoline intermediate under basic conditions. This intermediate is then dehydrated in the presence of trifluoroacetic anhydride (TFAA) and pyridine, followed by the addition of triethylamine (TEA) to yield the desired thiazole [57].

**Figure 18** shows a recent example of the Holzapfel-Meyers-Nicolau modification reported in the synthesis of 5-acylamino-1,3-thiazoles from α-chloroglycinates and thioamide derivatives [40]. ESI-MS monitoring revealed the presence of the hydroxy intermediate **X**. Dehydration of **X** results in the desired 5-acylaminothiazole derivative **56** in a high yield (87%). Phenylic substitutions were introduced successfully to the 2 and 4-positions using this approach [58].

### *3.4.4 Cook-Heilbron's synthesis*

Avadhani *et al* developed an efficient one-pot reaction for the preparation of 4-amino 2-aryl-5-substituted thiazoles. **Figure 19** presents the reaction of cyanamide **57** with dithioester **58a** or **58b** with excess NaH, followed by the addition of halocarbonyl derivative **59** to yield potent antiproliferative agents 4-amino-2-phenyl and 2-(thiophne-3-yl)- 5-(2,3,4-trimethoxybenzoyl)-thiazoles **60a** and **60b** in high yields

**Figure 18.** *Holzapfel-Meyers-Nicolau reaction between α-chloroglycinate* **54** *and thioamide* **55** *[58].* *Synthetic Strategies and Biological Activities of 1,5-Disubstituted Pyrazoles and 2,5-Disubstituted… DOI: http://dx.doi.org/10.5772/intechopen.108923*

**Figure 19.** *Cook-Heilbron's reaction between cyanamide* **57** *and dithioate derivative* **58** *[59].*

(77% and 81% respectively). The Thorpe-Ziegler-type reaction proceeds via basemediated intermolecular cyclization of N-cyanothioimidate intermediate **XI** [59].

The 2-methylthio and arylamino substitutions can be introduced at the 2-position using this method, while the 5-position supports ester, nitrile, and carbonyl substituents. The latter can be utilized to introduce reactive functionalities, expanding the possible range of substitutions achieved by this protocol. The novel methodology was further validated by the synthesis of 26 4-amino-2-(het)aryl/alkyl 5-substituted thiazole derivatives [59]. It should be noted that this example introduces the amino moiety to the 4-position. The 5-aminothiazoles can be synthesized from the reaction with 2-aminoacetonitrile instead of cyanamide.

#### *3.4.5 Lactic acid-mediated one-pot reaction*

**Figure 20** shows the one-pot Hantzsch synthesis of the 2-aminothiazole **63** using lactic acid as a green solvent and catalyst [60]. The ketone **61** was brominated *in-situ* followed by heterocyclization with thiourea **52** to produce the substituted aminothiazole **63**. Lactic acid was selected as a solvent and catalyst due to its ability to solubilize all the reactants, its increased product yield and shorter reaction times in comparison to acetic acid. Maximum yields of 2-aminothiazoles (up to 96%) were obtained when the temperature was increased from room temperature (45% in 1.2 h) to 90–100°C [60]. Lower yields were reported yields when strong deactivating groups were introduced (such as -NO2), likely due to the reduced *in-situ* formation of the α-brominated

**Figure 20.** *Lactic acid-mediated one-pot synthesis of 2-aminothiazoles [60].* ketone. Overall, this work developed an effective, rapid, and sustainable one-pot synthesis of 2-aminothiazoles in excellent yields [60].

#### *3.4.6 Aluminum oxide/PVA thin film-catalyzed reaction*

The catalytic activity of hybrid PVA/Al2O3 nanofilms in the synthesis of thiazole derivatives was recently reported by Riyadh *et al* [61]. The reaction between the thiosemicarbazone 2-benzylidenehydrazine **64** and the α-haloester ethyl-2-chloro-3-oxobutanoate **65** in the presence of the PVA/Al2O3 nanocomposite as a basic catalyst is demonstrated in **Figure 21**. Under thermal conditions, the optimal loading catalyst was 10 wt% and the desired compounds were obtained after 180 min [61].

**Figure 22** describes a plausible reaction mechanism where the Al2O3 particles act as a base in the deprotonation of the thiol group from carbothioamide tautomeric intermediate **XVIII**. The thiolate anion **XIX** then attacks α-halocarbonyl **65**,

#### **Figure 21.**

*Polyvinyl alcohol/aluminum oxide (PVA/Al2O3) thin film nanocomposite as a catalyst in the synthesis of 2,4,5-thiazoles [61].*

**Figure 22.** *Proposed mechanism of PVA/Al2O3-catalyzed reaction [61].* *Synthetic Strategies and Biological Activities of 1,5-Disubstituted Pyrazoles and 2,5-Disubstituted… DOI: http://dx.doi.org/10.5772/intechopen.108923*

displacing -Cl and generating the intermediate **XX**. The cyclocondensation of **XX** yielded the desired thiazole derivatives. The catalyst was recycled three times and recovered in excellent yields (90%) [61].
