Design Synthesis and Evaluation of Anticancer Pyrazole Derivatives of Chalcone Scaffold
Ms. Kedar M.S1, Dr. Shirbhate M.P2, Dr. Rajani Chauhan3, Dr. Suman Sharma4,
Dr. Amrita Verma5
1Lecturer, Amrutvahini Institute of Pharmacy, Sangamner
2Principal, Amrutvahini Institute of Pharmacy, Sangamner
3Associate Professor, Banasthali Vidhyapith Department of Pharmacy, Rajasthan
4Assistant Professor, Banasthali Vidhyapith Department of Pharmacy, Rajasthan
5Assistant Professor, Graphic Era Hill University, Bhimtal, Nainital
*Corresponding Author E-mail: 17vedant17@gmail.com
ABSTRACT:
Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms.[2] Notable drugs containing a pyrazole ring are celecoxib (Celebrex) and the anabolic steroid stanozolol. Chalcone is an aromatic ketone and an enone that forms the central core for a variety of important biological compounds, which are known collectively as chalcones or chalconoids. Chalcones (1,3-diaryl propenones), a family of small molecules that are naturally abundant in edible plants, have been found to have antitumor properties for specific cancer cell lines and to interfere in each step of carcinogenesis, including apoptosis.
1. INTRODUCTION:
Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbonatoms and two adjacent nitrogen atoms. Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugated acid 2.49 at 25 °C).[1] Pyrazoles are also a class of compounds that have the ring C3N2 with adjacent nitrogen atoms.[2] Notable drugs containing a pyrazole ring are celecoxib (Celebrex) and the anabolic steroid stanozolol.
Fig 1: Structure of pyrazole
Chalcone is an aromatic ketone and an enone that forms the central core for a variety of important biological compounds, which are known collectively as chalcones or chalconoids. Alternative names for chalcone include benzylideneacetophenone, phenyl styryl ketone, benzalacetophenone, β-phenylacrylophenone, γ-oxo-α,γ-diphenyl-α-propylene, and α-phenyl-β-benzoylethylene.
Fig 2: Structure of chalcone
2. ANTICANCER THERAPY:
Anticancer therapy, especially in veterinary medicine, was based and still relies almost exclusively on surgical therapy, although associated therapy has developed over the past decades: surgery and/or chemotherapy and/or radiotherapy, with the development of cryotherapy, immunotherapy and in general, the adoption of techniques and methodologies used in human oncology.
The therapeutic strategy should take into consideration three indispensable elements:
· The histological nature of the lesion;
· The assessment of the extension of the tumor process;
· The evaluation of the general disease state.
The pyrazoles diversely substituted by aromatic and heteroaromatic groups possess numerous biological activities, which makes them particularly interesting. The various access routes to the pyrazole nucleus have undergone numerous modifications since the first syntheses described by Knorr4 In this section, we will study this evolution and present the methods generally used to access substituted pyrazoles, that is to say. (Khalid Karrouchi et al. 2018)
Fig.3: Pharmaceutical Drugs Containing Pyrazole Unit
Chalcones (1,3-diaryl propenones), a family of small molecules that are naturally abundant in edible plants, have been found to have antitumor properties for specific cancer cell lines and to interfere in each step of carcinogenesis, including apoptosis1.For example, isoliquiritigenin is a chalcone that induces apoptosis in human hepatoma cells 5 and licochalcone is another chalcone that increases BAX and BAK levels and decreases levels of BCL-2 and BCL-X(L)6 (Sarah K Zingales et al .2016)
3. Synthesis of Pyrazole Derivative with Chalcone Scaffold:
3.1 A series of substituted chalcones and their corresponding pyrazoles were synthesized and evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines. Out of 93 compounds screened, some compounds showed marked activity. Compounds 4j, n and 4s were found to be the most promising in this study. SAR is also discussed7
3. 2 A novel series of 1-(2,4-dimethoxy-phenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-propenone (3) have been prepared by the Claisen–Schmidt condensation of 1-(2,4-dimethoxy-phenyl)-ethanone (1) and substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2). Substituted 1,3-diphenyl-1H-pyrazole-4-carbaldehydes (2) were prepared by Vilsmeir–Haack reaction on acetophenonephenylhydrazones to offer the target compounds.8
3. 3 A series of chalcones (1–9) and pyrazoles (10–18) was prepared to investigate their potential activity as Angiotensin I-Converting Enzyme (ACE) inhibitors. Their structures were verified by elemental analysis, UV, IR, MS, 1H NMR, 13C NMR, and 2D NMR experiments. Among tested compounds, chalcone 7exerted the highest activity with an IC50 value of 0.219 mM, while the most potent pyrazole was 15 (IC50 value of 0.213 mM).9
3.4 Various structural modifications of the pyrazole nucleus have been made to explore its characteristics and biological potential. The present work aims to review the use of molecular modeling in the designing of novel pyrazole analogs that may target various receptors such as protein kinase inhibitor, tyrosine kinase, Aurora-A kinase, tumor growth factor (TGF), cyclin dependent kinase (CDK) and fibroblast growth factor (FGF), which are significant for the management of cancer.( Kumar, H.,et al.)10
3.5 Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. (Sharma V et al.)11
3.6 Cancer remains as a prominent cause of death, worldwide. Numerous drugs that are currently in clinical practice have developed multidrug resistance along with fatal side effects. Therefore, the utilization of single-target therapy is incapable of providing an effective control on the malignant process. (Kerru N et al.)12
3. 7 There are various pyrazole derivatives are developed by linking pyrimidine, carboxyhydrazide as well as ferrocenyl molecule with the pyrazole cap and all are especially effective against lungs cell carcinoma (A549). Hitoshi et al prepared Pyrimidinyl pyrazole derivatives as a new scaffold of an anti-tumor agent, which also showed antiproliferative activity against human lung cancer cell lines and inhibited tubulin polymerization (Pal DI et al.)13
3.8 Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold remained a fascination among researchers in the 21st century due to its simple chemistry, ease of synthesis and a wide variety of promising biological activities. Several natural and (semi) synthetic chalcones have shown anti-cancer activity due to their inhibitory potential against various targets namely ABCG2/P-gp/BCRP, 5α-reductase, aromatase, 17-β-hydroxysteroid dehydrogenase, HDAC/Situin-1, proteasome, VEGF, VEGFR-2 kinase, MMP-2/9, JAK/STAT signaling pathways, CDC25B, tubulin, cathepsin-K, topoisomerase-II, Wnt, NF-κB, B-Raf and mTOR etc. (Mahapatra DK)14
3.10 Cancer is an inevitable matter of concern in the medicinal chemistry era. Chalcone is the well exploited scaffold in the anticancer domain. The molecular mechanism of chalcone at cellular level was explored in past decades. This mini review provides the most recent updates on anticancer potential of chalcones. (Das M et al.)16
3.11 A series of novel pyrazole-based chalcones have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxyphenyl)-1H-pyrazole (6). The structures of regioisomers 6 and 7 were determined by 2D 1H–1H COSY, 1H–13C HSQC and 1H–13C HMBC experiments. The newly synthesized compounds were tested for their inhibitory activity against COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. (Chavan HV,)17
3.12 Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. (Karthikeyan C et al.)18
3.13 The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. (Karrouchi K et al.)19
3.14 n an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes. (Alam R et al.)20
3.15 A combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, 1H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-α and IL-6(Bandgar BP et al.)21
4. PROPOSED TARGET STRUCTURE:
4.1 Synthesis of (2E)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-1,3-diphenylprop-2-en-1-one:
From the all literature review concluded that the proposed compound may be give the anticancer activity having pyrazole with chalcone moiety. The scheme given below for proposed target compounds.
5. CONCLUSION:
The pyrazoles diversely substituted by aromatic and heteroaromatic groups possess numerous biological activities, which makes them particularly interesting. A series of substituted chalcones and their pyrazoles derivatives will be synthesized from above given scheme and evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines.
6. REFERENCE:
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Received on 16.07.2019 Modified on 11.08.2019
Accepted on 05.09.2019 © RJPT All right reserved
Research J. Pharm. and Tech. 2020; 13(1): 342-346.
DOI: 10.5958/0974-360X.2020.00069.4