A Study of Synthesis, Characterization and Biological Evaluation of Pyrazolyl Diaryl Cyclohexenone Derivatives

The synthesis, characterization, and biological evaluation of pyrazolicchalcone, pyrazolylpyrazoline, and pyrazolyldiarylcyclohexanone derivatives are important areas of research in medicinal chemistry. ,Pyrazolicchalcones are a class of compounds that have been shown to exhibit a range of biological activities, including anti-inflammatory, antioxidant, and antimicrobial properties. These compounds are typically synthesized by the condensation of pyrazole with a carbonyl compound, such as an aldehyde or ketone, in the presence of a base catalyst. Pyrazolylpyrazolines are a class of compounds that are formed by the cyclization of pyrazole with an enone, such as chalcone. These compounds have been shown to exhibit a variety of biological activities, including anticancer, antitumor, and antifungal properties. Pyrazolyldiarylcyclohexanones are a class of compounds that are formed by the reaction of pyrazole with diarylcyclohexanones.

The heterocyclic chemical pyrazole consists of two neighboring nitrogen atoms in a five-membered ring structure. Heterocyclic compounds linked to pyrazole showed a wide range of chemotherapeutic activity. The biological effects they exhibited ranged from anti-inflammatory to anti-microbial to anti-malarial to anti- hypertensive to anti-tubercular to anti-viral to neuroprotective to anti-depressant to anti-cancer. Some pyrazole compounds have been shown to be a valuable entity in the creation of effective chemotherapeutic medicines, while others have found usage in clinical settings.

The promise of chalcone derivatives as chemotherapeutics has led to their study in large numbers, both naturally occurring and synthetically produced. They exhibited biological features such as those against bacteria, fungi, protozoa, malaria, leishmania, cancer, inflammation, cell division, invasion, and so on. Analogue 74 had an IC50 of 15.36 M against the MCF-7 cancer cell line. Indolylchalcone 75 was shown to be cytotoxic to the PaCa-2 cancer cell line, with an IC50 of 0.03 µM. The cytotoxicity of pyranochalcone 76 against HT-29 was determined to be 0.55 µM. The pyrazolicchalcone 77, as shown in recent research by Hawash et al., is cytotoxic to Huh7 cells with an IC50 value of 0.03 µM. The remarkable complementarity between the anticancer activity profiles of pyrazole and chalcone inspired us to attempt the synthesis of pyrazolicchalcones. Several cell lines, including cancerous Caco-2, MIA PaCa-2, and MCF-7 cells and normal NIH-3T3 cells, were tested for cytotoxicity in vitro.

Strocchi E (2012) Herein, we detailed the use of molecular modeling in the optimization of tiny pyrazole derivatives produced by 1,3-dipolar cycloaddition of nitrile imines and functionalized acetylenes for use as kinase inhibitors. We tested the two compounds in vitro for their biological activity on cell lines developed from HCC to determine their potential as anti-HCC agents. The compounds are attractive lead compounds for future SAR studies due to their inhibitory growth effectiveness (IC(50) 50-100 M) in the SNU449 cell line, as well as their ability to halt cell cycle progression and induce apoptosis. Wang G, (2014) Theantiproliferative effects of a newly of the left phenyl ring and an N-methyl-5-indoly group at t5-position of the right phenyl ring, showed the highecytotoxic activity against all tested cancer cell lineincluding those with a multidrug-resistant phenotype, wIC50 values ranging from 0.22 to 1.80M. Additionally, 4dramatically decreased tubulin polymerization and triggercell cycle arrest in the G2/M phase. 49b's interaction wthe tubulin colchicine binding site was confirmed molecular docking. 49b showed strong anticancer efficaagainst HepG2 human liver carcinoma in BALB/c numice in in vivo tests. These findings suggested that thechemicals are effective tubulin polymerization inhibitowhich might be used to treat cancer. Hawash MM, (2017) Sorafenib is the only FDA-approvchemotherapeutic treatment now available for liver cancpatients, however it can only extend life by a few monthsmost. Liver cancer has the second-highest fatality rateany malignancy. In this research, many compounds with structural similarities to pyrazolicchalcones were synthesized and tested for their efficacy as chemotherapeutic agents against hepatocellular carcinoma (HCC). Fourty-two alternative compounds were obtained by replacing the pyrazole moiety at C(4) with a chalcone moiety of varying substitution patterns and by modifying the pyrazole ring at C(3) with a variety of heteroaryl rings. The cytotoxicity of each of these substances was tested using the sulforhodamine B assay and with real-time cell growth monitoring. Compounds 39, 42, 49, and 52 were shown to have much higher cytotoxic effects than the standard chemotherapeutic medication 5-FU, as measured by their 50% inhibitory concentration (IC50) values, against all of the cancer cell lines examined. As a result, we decided to test these chemicals in a variety of HCC cell lines. Cell growth was inhibited and the cell cycle was arrested in HCC cells treated with chemicals 39, 42, 49, and 52, as determined by flow cytometric analysis and real-time cell growth monitoring. Consistent with these findings, western blotting of HCC cells treated with the chemicals revealed molecular alterations for cell cycle proteins. Specifically, p21 levels were found to rise independently of p53, while the levels of the major initiators of mitosis, Cyclin B1 and CDK1, were shown to decrease. In conclusion, chalcone derivatives 42 and 52 have strong bioactivities, as shown by their ability to modulate the expression of cell-cycle-related proteins and their subsequent ability to cause cell-cycle arrest in the HCC cell lines evaluated here. Harras MF (2018) Three distinct cancer cell lines, HCT116, UO-31, and HepG2, were used to test the cytotoxic activities of a series of newly synthesized 1,3,4-trisubstituted pyrazole derivatives. The cytotoxic activities of compounds 3b, 3d, 7b, and 9 were superior to those of the reference medication Sorafenib in all of the cancer cell lines evaluated. As a result, we decided to test these chemicals in a variety of HCC cell lines. The most effective

promoted apoptosis in HepG2 and Huh7 cells. Caspase-3 assays were performed, and the findings were consistent with the idea that the target chemicals' pro-apoptotic action was triggered by caspases-3. Furthermore, a CDK1 inhibition experiment was carried out, yielding IC50 values of 2.38 and 1.52 M for compounds 3b and 7b, respectively. Finally, the powerful bioactivities of the pyrazole derivatives 3b and 7b suggest that these compounds have great potential as future anticancer medicines. Mallia A (2020) When it comes to building heterocyclic compounds with therapeutic or industrial applications, chalcones continue to be held in high esteem. Preparative procedures for this useful class of compounds have benefited greatly from the development of synthetic routes for hybrid chalcones incorporating heteroaromatic components, particularly those based on green chemistry principles. Incorporating heteroaromatic components into hybrid chalcone construction has advanced in recent decades, and this paper details those developments while also highlighting ecologically friendly procedures used in their manufacture. Mohamed MF (2020) Lung cancer patients may benefit from a new chalcone series that has been created. The new series was validated using a variety of spectral analysis methods. The new chalcones' cytotoxic impact on the lung cancer cell line (A549) was measured using the MTT test. The two most efficient chalcones, 7b and 7c, were the subject of molecular docking research. Two chalcones, 7b and 7c, were investigated for their activity and influence on apoptosis of the A549 cell line using a variety of molecular methods.

To determine cell viability, the MTT test uses the fact

The chalcone-derived cyclic compounds known as di-aryl cyclohexenone derivatives are widely used for their antimicrobial properties. Our synthesis of pyrazolicchalcones 4a-i led us to the discovery of di-aryl cyclohexenone derivatives 8a-i, which we used in our study of chalcones' anticancer effects. The human cancer cell lines were used as test subjects for the pharmacological activity and cytotoxicity of all synthesised compounds. Chemistry To get di-aryl cyclohexenone derivatives 8a-i, pyrazolicchalcones 4a-i were treated with ethylacetoacetate in ethanolic KOH. Scheme showing the synthesis of the intended compounds.

Biology To ascertain the cytotoxicity of all heterocyclic derivatives 8a-i, in vitro MTT experiments were carried out on a panel of three human cancer cell lines (MCF-7 (human breast), NCI-H460 (human lung), HeLa (human cervix), and HEK-293T (human embryonic kidney cell) normal cell line). The M concentrations of the substances were utilised to calculate their IC50 values. The IC50 values are shown in Table 4.1 using etoposide as the reference chemical. According to their IC50 values, the majority of these substances shown moderate to significant cytotoxicity against the human cancer cell lines NCI-H460, HeLa, and MCF-7, but only minor toxicity towards the HEK-293T cell line. Given the medical standard of today Analogues 8d, 8e, 8f, and 8g have considerably enhanced cytotoxic effects as compared to etoposide.

Structure-activity relationship (SAR) studies were carried out to ascertain the impact of various substituents on the cytotoxic effects of the synthesised compounds. The most dangerous of the compounds tested was 8d, which has a Meta substituted Br group on the benzene ring. Nitrogen dioxide (NO2) substitutes in the benzene ring of metabolites 8f and 8g were efficient. Compounds 8d and 8f, both of which include a Meta substituted

CONCLUSION

Our studies have centered on the design of new heterocyclic anticancer chemicals that are linked to pyrazoles. The pyrazolicchalcones 4a-i have been synthesized, characterized, and tested for cytotoxicity in vitro. All of the substances showed low to moderate toxicity towards normal cells while having moderate to high cytotoxic effects against the cancer cell lines evaluated. Among the synthesized compounds tested for cytotoxicity, the analogues 4f, 4g, and 4h stood out in comparison to the gold standard medication etoposide.

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PhD Student, Kalinga University, Raipur (CG).