Synthesis and Biological Evaluation of Thiazole Derivatives

Thiazoles belong to the group of azole heterocycles. They are aromatic five-membered heterocycles containing one sulfur and one nitrogen atom. In recent years thiazoles, their derivatives, and isomers have gained considerable attention because of their broad applications in different fields, such as agrochemicals, industrial, and photographic sensitizers. Also, they have pharmaceutical and biological activities that include antimicrobial (sulfazole), antiretroviral (ritonavir), antifungal (abafungin), anticancer (tiazofurin), antidiabetic, anti-inflammatory, anti-Alzheimer, antihypertensive, antioxidant, and hepatoprotective activities. The compounds containing thiazole moieties are a prominent structural feature in a variety of natural products, such as vitamin B and penicillin. Thus, in this chapter several types of thiazole-based heterocyclic scaffolds such as monocyclic or bicyclic systems synthesis and their biological activities studies are presented. Furthermore modification of thiazole-based compounds at different positions to generate new molecules with potent antitumor, antioxidant, and antimicrobial activities is described.


Introduction
Thiazoles are five-membered heterocyclic compounds containing nitrogen and sulfur atoms with isothiazole isomer. Thiazoles are a basic scaffold found in many natural compounds as vitamin B1-thiamine, alkaloids, anabolic steroids, flavones [1].
The interest in the synthesis of compounds containing the thiazole moiety has been increasing steadily in view of their utility in the field of photosensitizers, rubber vulcanization [ , and chromophores [9, 10]. Moreover, thiazoles occupy a prominent place in current medicinal chemistry due to their wide range of applications in the field of drug design and discovery [11]. They appear in the bacitracin, penicillin antibiotics [12], and various synthetic drugs as short-acting sulfa drug sulfathiazole [1]. Also, they are used as an antidepressant drug (pramipexole) [13], antiulcer agent (nizatidine) [14], anti-inflammatory drug (meloxicam) [15], HIV/AIDS drug (ritonavir) [16], and cancer treatment drug (tiazofurin) [17]. In fact, thiazole is a more common component of FDA-approved pharmaceuticals than related five-membered heterocycles such as isothiazole, thiophene, furan, isoxazole, and oxazole. On the other hand, the metal complexes of thiazole are widely used in photocatalysis [18]. 1,3-Thiazoles undergo different types of reactions to yield various biologically active fused heterocyclic moieties as thiazolopyrimidine, imidazothiazoles, thiazolopyridine, etc. [19][20][21].

Synthesis strategies of 1,3-thiazole derivatives
Thiazole ring system were easily synthesized by well-known methods of Hantzsch [22], , and Gabriel [24]. A number of compounds may serve as nucleophilic reagent in this reaction, such as thioamides, thiourea, ammonium thiocarbamate or dithiocarbamate, and their derivatives. Hantzsch synthesized the simple thiazole nucleus in 1887 [25]. This synthesis approach involves cyclization and condensation of haloketones with thioamide, and it is considered the most widely popular process for the synthesis of thiazole moiety. In contrast, Gabriel synthesized thiazoles by treating α-acylaminoketones with stoichiometric amounts of P2S5 or Lawesson's reagent [26]. Also, Cook-Heilbron used versatile methods for the synthesis of substituted aminothiazoles involving the reaction of α-aminonitriles with dithioacids or esters, carbon disulfide, carbonyl sulfide, and isothiocyanates under mild conditions [27].
Lately, thiazole derivatives were synthesized in the presence of various catalysts [28-31] and with the use of a microwave irradiation technique [32].

Reaction with esters and salts of dithioacids
The salts or the esters of both dithioformic and dithiophenacetic acids were reacted with α-aminonitriles to give 5-aminothiazoles (2.3) in good yields [43] ( Figure 5).

Using microwave-assisted synthesis (MAOS)
The synthesis of thiazole derivatives involves vigorous reaction conditions and wastage of solvents and catalysts. To overcome these shortcomings, eco-friendly methods as microwave irradiation technique are commonly used for synthesis of  Azoles -Synthesis, Properties, Applications and Perspectives 4 thiazole derivatives [45]. Rapid and elegant synthesis of a series of thiazoles (2.5.1) uses microwave heating under solvent-free conditions [32, 46,47] (Figure 7).

One-pot multicomponent reaction in aqueous medium
Water is economically viable, nontoxic, and the most friendly reaction medium available, making it an environmentally acceptable solvent for the design and development of green chemistry technique. A three-component reaction of phenyl acetylene, N-bromosuccinimide, and thiourea in aqueous medium gave substituted thiazole derivatives (2.5.2) in good yield [48] (Figure 8).

Using silica-supported tungstosilisic acid
An efficient and green method has been developed for the synthesis of new substituted Hantzsch thiazole derivatives (2.5.3) by one-pot multicomponent procedure. 3-(Bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one was reacted with     thiourea and substituted benzaldehydes in the presence of silica-supported tungstosilisic acid as a catalyst under conventional heating or under ultrasonic irradiation technique [46,49] (Figure 9).

Miscellaneous methods
Hantzsch construction of thiazole derivatives (2.6) was established by the reaction of α-chloroglycinate esters with thioamides or thioureas. Targeted compounds are obtained from readily available and inexpensive building blocks through an environmentally benign process and without catalysts [50] ( Figure 10).
The C − H substitution reaction of thiazole by the catalysis of the palladium/ copper system is carried out in the presence of tetrabutylammonium fluoride under mild conditions. Various 2,5-diarylthiazole derivatives (2.6.1) were synthesized in good yields [51] (Figure 11).    The mixtures of thiourea and acetophenone were treated with various oxidizing gents as sulfuryl chloride, chlorosulfonic acid, thionyl chloride, sulfur monochloride, sulfur trioxide, sulfuric acid, nitric acid, and sulfur. In each case a large amount of 2-amino-4-phenylthiazole (2.7) was obtained [52] (Figure 12).
In another approach towards triple-negative breast cancer, Zhou et al. synthesized and optimized a series of hybrids of 2,4-diaminopyrimidine and thiazole derivatives (3.1.4). These compounds showed anti-proliferative properties against two breast cancer cell lines, MCF-7 and MDA-MB-231. Several of these compounds also exhibited potent activities against tumor cell colony [76] (Figure 16).
Dae-Kee K et al. produced a set of 5-(pyridin-2-yl)thiazoles enclosing a p-and/ or m-carboxamide or carbonitrile-substituted phenylmethylamino moiety at position 2 of the thiazole ring (3.1.6). This series is evaluated for its ALK5 inhibitory activity [78,79] (Figure 18).  A series of 2,4-disubstituted thiazole compounds containing N-n-butyl or N-cyclohexyl thioureido synthon at position 2 and N-substituted thiosemicarbazone moiety (3.1.7) at position 4 were synthesized by HI El-Subbagh et al. and verified for their antitumor activity. All of the established derivatives revealed antineoplastic activity [80] (Figure 19).
El-Borai et al. synthesized a series of 2 6-substituted-3-(pyridin-3-yl) imidazo[2,1-b]thiazole (3.1.9) which are tested for anticancer activity against human cancer cell lines HEPG2 (liver cancer) and MCF7 using sulforhodamine B Figure 13. Structure of compound 3.1.1.   Figure 14. Structure of compound 3.1.2.   Figure 15. Structure of compound 3.1.3. (SRB) assay. All the synthesized compounds displayed more anticancer activity towards the selected cell line cancer, suggesting that it might be a potential alternative agent for human hepatic cancer therapy [82] (Figure 21).

Antimicrobial activity
Fungal and bacterial resistance to antimicrobial drugs is increasing rapidly due to nonselective antimicrobial activities and a limited number of drugs. To overcome this situation, several molecules containing thiazole are synthesized to treat bacterial and fungal infections [83,84].     (Figure 23).
A series of thiazolyl thiazolidine-2,4-dione derivatives were synthesized by Dundar et al. These compounds were screened for their antibacterial and antifungal activities against methicillin-resistant S. aureus, E. coli, and C. albicans. All the compounds particularly (3.2.4) were found to be moderately potent against screened microorganisms [86] (Figure 24).
Bera et al. Synthesized pyridinyl thiazole ligand having hydrazone moiety and its cobalt complex. Both ligand and its complex were tested for antibacterial properties towards Gram-positive and Gram-negative bacteria. The results revealed that the ligand (3.2.6) exhibited excellent antibacterial activity. The presence of pyridinium ion in the ligand showed increased solubility of the ligand which enhances the cell penetrating ability and cell binding activity of the ligand. Hydrolysis of ligand decreases the pH of the medium which facilitates easy penetration of ligand into the cell [88] (Figure 26).    compounds 3.2.1 and 3.2.2.

Antioxidant activity
Antioxidants are of great interest due to their participation in important biological and industrial processes. They are generated in the human body and may cause damage to lipids, proteins, and DNA and thus may lead to various diseases such as cancer, atherosclerosis, diabetes, cirrhosis, and Alzheimer's and inflammatory diseases [91]. Thiazole and derivatives are the core structure in a variety of pharmaceuticals with a wide range of biological activity [92][93][94].   The antioxidant potential compounds (3.4.1) was evaluated by spectrophotometric method, using DPPH radical or Fe (TPTZ) 3+ complex, and EPR spectroscopy and revealed that the synthesized compounds were showing potent antioxidant activity [95] (Figure 29).
Gouda et al. synthesized 2-amino thiazole derivatives and evaluated their antioxidant activity. They reported that the three compounds (3.4.3) showed potent antioxidant activity after postulating the structure-activity relationship (SAR) [97] (Figure 31).

Conclusion
Thiazole moieties have occupied a pivotal position in the modern organic and medicinal chemistry due to its broad-spectrum pharmacological and medicinal activities such as antimicrobial, anticancer, and antioxidant. The presence of thiazole ring in many drugs such as penicillin, pramipexole, tiazofurin, meloxicam, and nizatidine motivates the chemists to design new thiazole scaffolds. Thiazole nucleus exhibited an important role in finding new leads and drugs for various diseases. This chapter has illustrated the commonly used approaches to synthesize subsisted thiazole derivatives, described their key electronic properties, and highlighted their most important chemical reactivity. A particular focus has been on the use of thiazole in dyes and their metal complexes and miscellaneous applications of thiazole dyes. Also we have focused our attention on the biological application of thiazole derivatives.

FDA
Food and Drug Administration (USA) SAR structure-activity relationships MAOS microwave-assisted synthesis HTIB [hydroxy-(tosyloxy)-iodo] benzene TBAF tetrabutylammonium fluoride © 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. [