Thiazole is a heterocyclic organic compound characterized by its five-membered ring containing both sulfur and nitrogen atoms. Its chemical formula is C3H3NS, and it has gained significant attention due to its diverse biological activities and applications in drug development. Thiazole has a planar, aromatic ring structure with a sulfur and nitrogen atom adjacent to each other. This ring system imparts unique electronic properties, influencing its reactivity and interaction with biological targets. The electronic distribution and ring tension in thiazole contribute to its ability to form various derivatives with altered biological properties.

 Hantzsch thiazole synthesis

Hantzsch thiazole synthesis is one of the most reliable ways of synthesizing thiazoles. It is the condensation of ?-haloaldehydes or ketones with thioureas in neutral, anhydrous solvents to form 2-aminothiazoles. Similarly, condensation between thiourea and chloroacetaldehyde results in the formation of 2-aminothiazole. The reaction proceeds through the nucleophilic attack of the nitrogen atom via its lone pair of electrons on the carbon adjacent to the chlorine that is electrophilic (the electrophilicity of the carbon atom is attributed to the -I effect of the chlorine atom), followed by cyclization.

BIOLOGICAL ACTIVITIES

Anti- inflammatory activity [9]

S.N Thore, Sunil V Gupta, Kamalkishor G. Baheti synthesized thiazole derivatives which exhibited significant analgesic and anti-inflammatory activities. Among all the synthesized compounds, those possessing 1, 3, 4-oxadiazole2(3H)-thione (compound 11 and compound 14) and pyrazole (compound 15 and compound 16) at position 4 of thiazole (Scheme 2) exhibited more prominent and consistent anti-inflammatory activity than that of the standard drug diclofenac sodium. The compound 9 showed moderate anti-inflammatory activity. The compounds 11 and 14 exhibited good activities in both in silico(docking) and in vivo studies.

Anti-inflammatory activity was evaluated by the carrageenan-induced paw oedema test in rats (Winter et al., 1962) at equimolar doses equivalent to 25mg/kg (diclofenac sodium) body weight. The anti-inflammatory activity data (Table 1) indicated that all the test compounds protected rats from carrageenan-induced inflammation moderately at 1 h of reaction time with increased activity at 2 h. Decline in activity was observed at 3 h. All the compounds in the series (compound 6 to compound 16) exhibited the anti-inflammatory activity in the range of 14–45 ?ter 1 h and 21–60 ?ter 3 h. The compounds 14 and 15 exhibited 44 and 45 % anti-inflammatory activities, respectively, whereas standard diclofenac sodium showed 40 ?tivity at 1 h of study. The same compounds showed 55 and 60 ?tivities at 3 h, whereas standard diclofenac sodium exhibited 55 ?tivity at 3 h. The structural correlation with anti-inflammatory activity showed that compounds with 1, 3, 4-oxadiazole-2(3H)-one, and pyrazole moiety showed better activity.

Analgesic activity [9,10]     

G. Saravanan, V. Alagarsamy, C.R. Prakash, P. Dinesh Kumar and T. Panneer Selvam synthesized a series of thiazole and pyrazole derivatives to study their analgesic effect. According to the literature survey thiazoles were reported to possess anti- microbial, analgesic , anti-inflammatory , anti- cancer, anti-tubercular and anti-diuretic activity. The title compounds (8a to 8j)  were synthesized by incorporation of pyrazole moiety at 2nd position of position of 2- hydrazinyl-N-(4-phenylthiazol-2-yl) acetamide (5) by treating with chalcones (7a to 7j). The 2-hydrazinyl-N-(4- phenylthiazol-2-yl) acetamide (5) was synthesized from 2- amino-4-phenyl thiazole (3) through 2-chloro-N-(4-phenyl thiazol-2-yl) acetamide (4).

The results of analgesic activity indicate that all the test compounds exhibited significant activity. When compared with standard drug (Pentazocin ,10 mg/kg) the compounds 8c and 8e exhibited comparable analgesic activity at 100 mg/kg. Compounds 8f, 8j, 8a and 8b exhibited moderate analgesic activity. Among the compounds synthesized compound 8d exhibited lowest analgesic activity. From the above results it may concluded that compounds containing electron donating groups exhibits better activity than electron withdrawing groups.

Anti-microbial activity [11]

In 2014, Liaras and co-workers synthesized two thiazole-based aminopyrimidine derivatives and eight N-phenylpyrazoline derivatives. Ten derivatives were tested against 9 g-positive and negative bacteria. The evaluations showed all structures have antibacterial activities. In addition, two compounds (1a and 1b) among all compounds (Table 3) had excellent activity. Streptomycin and ampicillin were used as reference drugs. Most of the derivatives showed comparable or better activities than the reference drugs. Among all derivatives, compound 1a had the best activity. Compound 1b showed the best inhibitory effect against gram-positive bacteria. The best antibacterial activity against gram-positive and negative bacteria showed by compound 1a. In addition, compound 2d displayed the lowest antibacterial activity, and had no activity against En. cloacae. Also, all derivatives had potent activity against S. aureus and L. monocytogenes compared to streptomycin (except compound 2 g). In the case of compounds 2a-h, compounds 2e, 2f and 2 h increased the activity in comparison with compound 2a, while compounds 2d and 2 g showed the opposite effect.

Anti-oxidant activity [12]

Vladimir N. Koshelev, Olga V. Primerova, Stepan V. Vorobyev, Anna S. Stupnikova and Ludmila V. Ivanova conducted a study in which a series of thiazoles and thiazolines were synthesized from four thiosemicarbazones with phenol scaffold (Scheme 4). The target compound 1 to compound 5 were prepared as it is shown in Scheme 3 and 4. Initially, the number of thiosemicarbazones was synthesized by the condensation of thiosemicarbazide and series of aldehydes: formylresorcinol-1a; vanillin-1b; 2,3-dihydroxy-4,6-ditert-butylbenzaldehyde-1c; and 4-hydroxy-3,5-di-tert-butylbenzaldehyde-1d.

Resorcinol derivatives showed a high iron-reducing activity among thiazoles, and alkylated catechol derivatives showed a high iron-reducing activity among thiazolidinones. Thiazolidinones , containing a carboxyl group, showed the greatest activity in both ABTS  assay and Feric ion reducing capacity assay . In addition, both types of activity increase with the introduction of the coumarin moiety.

Anti-cancer activity [13,14,15]

Fawziah A. Al-Salmi , Abdulmohsen H. Alrohaimi , Mohammed El Behery , Walaa Megahed , Ola A. Abu Ali , Fahmy G. Elsaid  , Eman Fayad  , Faten Z. Mohammed  and Akaber T. Keshta  developed and designed a safe and efficient anticancer drug, a novel series of thiazole derivatives (compounds 4a–c) and their acetyl derivative (compound 5) were synthesized (Scheme 5) through the reaction of thiosemicarbazone with chloroacetyl chloride, followed by cyclization with boiling ethanol in the presence of fused sodium acetate. Acetyl derivative (compound 5) was obtained via the acetylation of 4a with acetic anhydride. Utilizing elemental analyses and spectroscopic methods (IR and NMR), the structures of the synthesized compounds were verified. Using the MTT assay, all of the synthesized thiazole derivatives (compounds 4a–c) and compound 5 suppressed the growth of the cancer cell lines MCF-7 and HepG2. Compound 4c was examined in vitro using the VEGFR-2 enzyme assay, cell cycle analysis, and Annexin V FITC/PI assay. Compound 4c exhibited promising and potential antiproliferative, cell cycle arrest, and apoptosis activation of MCF-7 cancer cell lines compared to the reference drug and MCF-7 control.

In Vitro Cytotoxic Activity against Breast Cancer and Liver Cell Lines (MCF-7 and HepG2)

The MTT assay was used to determine the synthetic compounds’ (4a–c) and 5 in vitro cytotoxic activity (IC50): MCF-7 for breast cancer and HepG2 for liver cancer, and Staurosporine (STU) was used as the positive control drug. Their findings revealed that all synthesized thiazole derivatives (4a–c) and 5 exhibited antiproliferative activity of MCF-7 and HepG2 cells compared to the standard drug because of the thiazole moiety in their structure, which contains sulfur and nitrogen. The introduction of different substitutions and replacements on 2-(4-hydroxybenzylidene) (Scheme 5) may, in turn, increase or decrease the IC50 of the synthesized compounds (4a–c) and 5, as shown in (Table 4). Consequently, compound 4c, which contains a substitution on 2-(4-hydroxybenzylidene) (R=NH=NH-Ph), showed efficient cytotoxic activity toward MCF-7 and HepG2, with IC50 values 2.57 ± 0.16 ?M and 7.26 ± 0.44 ?M, respectively, followed by 12.7 ± 0.77 ?M and 6.69 ± 0.41 ?M, respectively, for compound 4a, which does not contain any substitutions on 2-(4-hydroxybenzylidene) (R=H) compared to 6.77 ± 0.41 ?M and 8.4 ± 0.51 ?M, respectively, of the standard drug