Review on Thiazolo-Triazole as a Promising Anticancer agent
Kale Jyoti D.*, Pravin B. Akolkar
Department of Pharmaceutical Chemistry, Rashtriya College of Pharmacy, Kannad.
*Corresponding Author E-mail: jyotikale703@gmail.com, pravinakolkar4@gmail.com
ABSTRACT
Thiazolo-Triazole is a fused ring heterocyclic system consisting of three nitrogen atoms and one Sulphur atom shows wide range of biological activities. Cancer is the second leading cause of death worldwide. In past few decades, there has been a crucial necessity for the design and development of innovative anticancer drugs that can diminish the serious health problems and unwanted side effects associated with presently used anticancer drugs. Many anticancer drugs are commercially accessible, but nonexistence of selectivity, target specificity, cytotoxicity, and development of resistance lead to serious side effects. Several experiments have been going on to develop compounds with negligible or no side effects. The thiazole and triazole heterocyclic are well-recognized to possess abundant pharmacological activities, including predominantly anticancer, as revealed by various investigations on anticancer compounds and the latest research findings pointed out that to study the anticancer potential of thiazolo-triazole compounds in single scaffold.
Keywords: Thiazole, Triazole, Anticancer, Heterocycles, Design.
INTRODUCTION
Design and synthesis of novel small molecules which can specifically block some targets in tumor cells are in perspective direction in modern medicinal chemistry. Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen. The term thiazole also refers to a large family of derivatives. Thiazole itself is a pale-yellow liquid with a pyridine-like odor and the molecular formula C3H3NS. The thiazole ring is notable as a component of the vitamin thiamin.
Triazoles, also known as pyrrole diazoles, are a class of organic heterocycles containing three nitrogen atoms and two carbon atoms in non-adjacent positions. In 1885, Bladin was the first scientist to name the carbon-nitrogen ring system triazole.
1,2,4-triazole (the ligand in the coordinating compound, sometimes using the abbreviation of Htrz) is one of the few isomeric compounds, the molecular formula is C2H3N3, called triazoles, is a compound composed of two carbon atoms Composed of five-membered rings, three nitrogen atoms. 1,2,4-triazoles and their derivatives have a wide range of applications. 1, 2,4-triazoles are planar molecules.1-4
Chemistry:
Thiazole is a five-member heterocyclic compound containing nitrogen and Sulphur atom. The structure of thiazole is reflected as the resonance amalgam of the subsequent resonating structures (Figure 1). However, some of the resonting structures are also probable with the contribution of d-orbitals of the sulfur atom
Triazoles, also known as pyrrole diazoles, are a class of organic heterocycles containing three nitrogen atoms and two carbon atoms in non-adjacent positions. In 1885, Bladin was the first scientist to name the carbon-nitrogen ring system triazole. Triazoles can form hydrogen bonds. This property is responsible for increasing the binding to the biomolecular target as well as the solubility of the compound. Triazoles can act as attractive linkers to connect two pharmacophores to form innovative bifunctional drugs. Therefore, these compounds are becoming increasingly useful and important in building bioactive and functional molecules.4
Aromaticity and Stability:
Aromaticity is the main reason of stability of triazole nucleus. An aromatic sextet is formed by donation of one π electron from each atom connected by double bonds, in addition of the remaining two electrons from a nitrogen atom. Also, triazole nucleus is stabilized by resonance that it can be represented by tautomeric forms.3-4,
Tautomerism in Triazoles:
Tautomerism is possible in both the structural isomers of triazoles. Chapter 4 Selection of Ligand Skeleton.
Tautomerism in 1,2,3-triazoles:
1,2,3-Triazoles have two tautomeric forms, 1H-1,2,3-triazole and 2H-1,2,3-triazole.
Tautomerism in 1,2,4-triazoles:
1, 2, 4-Triazoles have two tautomeric forms: 1H-1, 2, 4- triazole and 4H-1,2,4-triazole. Many studies have been indicated that is tautomer more sTable than tautomer.4-5
Structure of thiazolo-triazole:
Methods of synthesis of Triazole:
1. Einhorn-Brunner reaction:
The synthesis of 1,2,4-triazoles by condensation between hydrazines or mono substituted hydrazine and diacylamines in the presence of weak acid is known as the Einhorn–Brunner reaction. For example: N-formyl benzamide and phenyl hydrazine gave 1,5-diphenyl-1,2,4-triazole. 4-5
2. Pellizzari Reaction:
The mixture of amide and hydrazide to synthesize 1,2,4-triazole derivatives is generally called the Pellizzari reaction.
Heating a mixture of formamide and hydrazine hydrochloride with KOH has been reported to produce 1,2,4-triazoles. For example, benzamide and benzohydrazide give 3,5-diphenyl-1,2,4-triazoles.4-8
General Scheme for Synthesis of Triazole:
Step-I Synthesis of Aroyl Chloride:
1. A mixture of 0.2 mol carboxylic acid and 0.4 mol Thionyl chloride (SOCl2) is heated slowly (~ 3 hrs) to reflux temperature which is maintain until gas release ceases.
2. The excess of Thionyl chloride is removed by evaporating it.
3. The acid chloride are used as such without any purification in the next step.
Step II) Synthesis of Aroyl thiosemicarbazone:
1. 0.1 mol of thio semicarbazide in 50 ml of NN Dimethyl formamide and 0.11 mol of pyridine, 0.1 mol of acid chloride is dissolved under stirring at room temperature.
2. Stirred the reaction mixture continue upto 45 minutes at room temperature and 90 min at about 500C.
3. The reaction mixture poured into 250 ml of 30% HCL.
4. The formed was filtered, washed with water and characterized by TLC n-hexane: ethyl acetate (2:1).
III) Synthesis of Substituted Triazole:
1. A mixture of 0.05 mol of Aroyl thio semi carbazide in ml of 1.4 M Sodium Hydroxide (NaOH) in ethyl alcohol is heated at reflux 6 – 7 hrs. until raw material is consumed (Chromatographic control).
2. After reflux evaporate the ethyl alcohol.
3. The semi-solid residue is dissolved in 200 ml of water.
4. After hot discoloration with activated carbon, the filtrate is cool and brought to PH = 1 with HCL separated by filtration and recrystallized by ethanol.
5. Characterization is carried out by TLC n-hexane: ethyl acetate (2:1).
General procedure for the synthesis of 5-substituted-1,2,4-traizole-thione derivatives (6a-g):
To 0.01 mol of 7-((5-mercapto-4H-1,2,4-triazol-3-yl) methoxy)-4-methyl-2H-chromen-2-one 5, 0.01 mol of 2-bromo-1-substituted-ethanone were added in the presence of 0.015 mol of KOH in absolute ethanol and refluxed for 10 h in presence of phenyl propanol amine. The reaction mixture was cooled and poured onto crushed ice. The resulting solids were filtered, dried and recrystallized from mixture of ethanol and dimethyl formamide (DMF).8-12
Synthetic Route:
1.
2.
3.
Table No. 1: Pharmacological Anticancer Activity
|
Sr. No. |
Author |
Structure |
Activity |
Reference |
|
1. |
Roman Lesyk et al; 2007 |
|
Anticancer activity |
13 |
|
2 |
Jean-François Riou et al;2009 |
|
Anticancer activity |
14 |
|
4. |
Serhii Holota et al; 2021 |
|
Anticancer (Prostate cancer Activity) |
15 |
|
5. |
Jamal El Bakali, Jean- Francois Riou et al; 2009 |
|
Antitumor activity Tumor cancer |
16 |
|
6. |
Ahmed H. Abdelazeem et al; 2021 |
|
Antitumor activity Tumor cancer |
17 |
|
7. |
Sherif A.F. Rostom et al; 2017 |
|
Antitumor activity Tumor cancer (breast epithelial cell line) |
18 |
|
8. |
Ahmed H. Abdelazeem et al; 2020 |
|
Antitumor activity Glioma cell line, Renal cancer |
19 |
CONCLUSION:
Design and synthesis of thiazolo-triazole can be useful as anticancer activity. An attempt is made to focus on some synthetic methods of Thiazolo-Triazoles including Regioselective and electro synthesis. It can act as an important tool for medicinal chemists to develop newer compounds possessing Thiazolo-Triazole moiety that could be better agents in terms of efficacy and safety.
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Received on 21.03.2024 Modified on 11.04.2024
Accepted on 17.05.2024 ©AJRC All right reserved
Asian J. Research Chem. 2024; 17(3):169-173.