INTRODUCTION:

Worldwide one of the most common diseases is cancer. The accelerated growth and multiplication of malignant cell through a process called metastasis called cancer.The defective alteration to DNA within the aberrant cells can be brought on by substances that cause cancer . The aberrant cells have a capacity to proliferate and infiltrate surrounding tissues. Globally cancer mortality was 97 million in 2022 with over 20 million new cases. The three most popular forms of treatment are radiotherapy, chemotherapy and surgery.

For most type of tumor however no cancer treatment is 100 percent efficient since chemotherapy drugs have significant side effects, poor selectivity and high toxicity.^1-3 It is necessary to design novel anticancer treatments based on creative scaffolds chemotherapy does however have certain drawbacks including poor selectivity, genotoxicity, high cost and limited efficacy. ^4,5 Furthermore, it damages healthy body cells and produces organ toxicity, which decreases the quality of life for cancer patients. The need to develop new chemotherapy medications that target cancer cells more precisely and have fewer side effects has been confirmed by the fact that, despite advancements in chemotherapy, there are currently no medications that particularly target cancer cells. Optimizing treatment with targeted therapy compounds, which target specific enzymes, growth factor receptors, and signal transducers to disrupt various oncogenic cellular processes, along with other strategies enabled by translational medicine advancements, may improve patient outcomes.^6,7

FDA-approved drugs targeting specific proteins include: for EGFR, Geftinib, Erlotinib, Afatinib, Dacomitinib, Osimertinib, Cetuximab, and Panitumumab; for BRAF, Dabrafenib, Vemurafenib, and Encorafenib; for VEGF, Bevacizumab, Ziv-aflibercept, and Ramucirumab; for HER2, Tucatinib in combination with Trastuzumab, and Lapatinib; for MET, Cabozantinib, Tepotinib, Capmatinib, and Crizotinib; for MEK, Trametinib; for ALK, Crizotinib, Alectinib, Ceritinib, Brigatinib, and Lorlatinib; and for CYP17, Abiraterone acetate.^6-9

Oncogenic changes in cell signaling, particularly in proteins that regulate cell growth, division, and development, contribute to tumorigenesis. Protein tyrosine kinases (PTKs), which control these processes, are critical in normal cells but can become dysfunctional through mutations or genetic alterations, leading to cancer. One promising cancer treatment strategy targets the epidermal growth factor receptor (EGFR), a key PTK.^10-12 Inhibiting EGFR kinase with small molecules offers potential therapeutic benefits, ideally with minimal side effects. Recent studies have explored hybrid compounds, such as chalcones, for their anticancer properties.¹³ Nitrogen-containing heterocyclic compounds, like pyrazoline and pyrimidine, have shown significant biological activity, particularly in cancer treatment.¹⁴Pyrimidines, important in nucleic acid synthesis, are of particular interest. Molecular hybridization, which combines biologically active compounds into one structure, has emerged as a strategy to create more effective anticancer agents.^15-17 Depending on where the double bond resides, pyrazoline can take one of three forms: Three pyrazolines: 1) (1), 2) (2), and 3) 1) 3-pyrazoline 2. The most desirable and significant type of pyrazoline for regular research.

Pyrazolines are reduced derivatives of pyrazoles, with pyrazolidine being the fully reduced form. The unique envelope shape of the five-membered dihydropyrazole ring, where the C5 atom deviates from the planar arrangement, was discovered via X-ray analysis. These heterocyclic compounds, abundant in nature as alkaloids, vitamins, and other biological molecules, are important in organic synthesis.¹⁸Pyrazolines and their derivatives exhibit a range of biological activities, including antimicrobial¹⁹anti-inflammatory^20,21, antinociceptive, antitubercular²² antimalarial, antifungal antibacterial²³, anti-amoebic, anticancer ²⁴. Many pyrazoline-containing drugs, such as antipyrine, are clinically approved for treating various diseases. These compounds also show activity against enzymes like MAO, carbonic anhydrase, aldose reductase, and EGFR tyrosine kinase, and have been used in treatments for conditions like inflammation, pain, and fever.

Pyrazolines play a key role in various disorders, including cancer, by inhibiting receptor tyrosine kinases (RTKs) like EGFR (Epidermal Growth Factor Receptor Tyrosine Kinase).²⁵Studies have shown that pyrazoline derivatives can effectively target EGFR, a crucial regulator of cell processes such as division, growth, and apoptosis. EGFR mutations are common in cancers like hepatocellular carcinoma, breast cancer, lung cancer, and others. First-generation EGFR inhibitors, such as gefitinib and erlotinib, are approved for treating EGFR-mutant non-small cell lung cancer (NSCLC). The molecular understanding of EGFR signaling is advancing, highlighting its potential as a target for cancer therapies.^26-28

UPDATED DEVELOPMENT OF PYRAZOLINE AS EGFR INHIBITORS:

Server et.al. synthesized new thiazolyl-pyrazoline derivatives and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. Compound (1) 4-(4-(5-(4-chlorophenyl)-1-(4-(4-fluorophenyl)thiazol-2-yl)-4,5-dihydro-1H-pyrazol-3 yl)phenyl)morpholine (2), 4-(2-(5-(4-chlorophenyl)-3-(4-morpholinophenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4-yl)benzonitrile and (3) 4-(2-(5-(4-chlorophenyl)-3-(4-(piperidin-1-yl)phenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4-yl)benzonitrile were discovered to be the most effective anticancer agents when compared to erlotinib against the A549 and MCF-7 cell lines. Comparing compounds 2 and 3 to erlotinib (IC₅₀ ¼ 0.05 ± 0.01 mM), the results showed that compounds 2 and 3 significantly reduced EGFR and caused apoptosis in A549 and MCF-7 cell lines (IC₅₀ values of 4.34 ± 0.66 mM and 4.71 ± 0.84 mM, respectively). Furthermore, compound 2 was found to be a dual EGFR and HER2 inhibitor, as evidenced by its notable inhibition of HER2 (IC₅₀ value of 2.28 ± 0.53 mM).²⁹

1 2

Wahyuningsih et al. synthesized N-acetyl pyrazoline derivatives with methoxy and chloro/hydroxyl substituents and tested for cytotoxicity. A study on the cytotoxicity of pyrazoline compound 4 on breast cancer cell lines MCF7 having IC₅₀ 40.47 µg/ml, T47D having IC₅₀ 26.51 µg/ml, and HeLa having IC₅₀ 31.19 µg/ml revealed that it had modest activity against these cell lines. Pyrazoline 5 exhibits moderate activity against MCF7, with an IC₅₀ of 94.02 µg/ml. A docking study revealed the hydrogen bonding and π-cation interactions between pyrazolines and the EGFR receptor.³⁰

4 5

George et al. produced quinoline derivatives 6, 7, quinolinyl based pyrazolines, and quinolinyl pyrazolinyl thiazole hybrids and determined their capacity to inhibit the growth of MCF-7, HeLa, and DLD1 cancer cell lines in addition to normal fibroblast WI-38,. Eight substances were evaluated for their efficacy as EGFR inhibitors. These substances were harmless for the normal cell line but produced higher cytotoxicity against DLD1. When compared to gefitinib (IC₅₀ = 29.16 nM), they demonstrated inhibitory action at the nanomolar level, particularly for compounds 6 and 7.³¹

6 7

Adnin et al. produce N-phenylpyrazoline derivatives, which were clarified for spectroscopic investigation, by cyclocondensing phenylhydrazine and suitable chalcones. WiDr and T47D, two colorectal and breast cancer cell lines, were used to test their anticancer activities. Compound 8 4-(3-(4-chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl)-2-methoxyphenol having IC₅₀ value of 13.11 μg/mL in T47D cell line and 3.29 μg/mL in WiDr cell line, became known to be the most potent compound. To assess how each drug interacted with the EGFR receptor on cancer cells, a docking study was carried out. Because compound 8 has a hydroxyl group on its structure, it is the only examined chemical that interacts with the MET769 residue through hydrogen bonding.³²

Aktar et.al. created a novel class of pyrazole compounds connected to benzimidazoles. The in vitro anticancer properties of all the produced compounds were evaluated using this human cancer cell lines: MCF-7, HaCaT, MDA-MB231, A549, and HepG2. For every drug, EGFR receptor inhibitory effects were tested. Comparing Compound 9 to other compounds in the series, Compound 9 had the highest efficacy against lung cancer cell lines (IC₅₀ = 2.2 mM) and the highest affinity for binding EGFR (IC₅₀ = 0.97 mM). Compound 17 caused a substantial G2/M phase arrest, which halted the development of A549 cancer cells. Compound 9 was bound to the EGFR's active pocket (PDB 1M17) in molecular docking studies. It has two p-p interactions and five important hydrogen bonds, with binding energies of DG = 34.581 Kcal/mol. ³³

Nawaz et.al. created and manufactured pyrazoline-linked carboxamide compounds, then assessed their potential for inhibiting the EGFR kinase, exhibiting anticancer properties, and posing a risk of apoptosis and cardiomyopathy. Compounds 10 and 11 inhibit EGFR kinase at 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. According to the findings, some synthetic compounds exhibited notable inhibitory effect. Compounds 10 and 11 demonstrated more cytotoxicity against A549 cancer cells than doxorubicin, with IC₅₀ values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Furthermore, compounds 15 and 16 caused the cancer cell A549 to undergo apoptosis. According to the findings of molecular docking experiments, compounds 10 and 11 could attach to the hinge area of the epidermal growth factor receptor kinase adenosine triphosphate-binding site, just like erlotinib, the medication of choice. Thus, the present study shows that compounds 10 and 11 exhibit potent anticancer properties in vitro when applied to the human non-small-cell lung carcinoma cell line A549. These results can be explored in more detail using both animal models and additional cancer cell lines.³⁴

Alkamaly et al. developed new derivatives of the pyrazoline scaffold and examined their cytotoxicity against PC-3 cells, HepG2 cells, and MDA-MB-231-231 breast carcinoma cells. The compounds with the highest levels of activity, 12, 13, 14 demonstrated crucial and exhaustive anticancer approach with IC₅₀ values of 1.30–7.18 μM, in contrast to doxorubicin, which had an IC₅₀ of 5.12–7.33 μM. .³⁵

12 13

Abdelsalam et al. synthesized the novel series of thiazolyl-pyrazoline compounds, for the two receptor tyrosine kinases, EGFR having IC₅₀ 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively and VEGFR-2 having IC₅₀ 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively, compounds 15 and 16 had strong and specific inhibitory action. When thiazolyl-pyrazolines were tested against non-small lung cancer cells (NSCLC), the strongest anti-proliferative efficacy was reported. The compounds 15 and 16 demonstrated significant effectiveness against the A549 having IC₅₀ 4.2 and 2.9 mM, respectively and H441 having IC₅₀ 4.8 and 3.8 mM.³⁶

15 16

Al-Anazi et al. developed and synthesized novel derivatives of chalcone, pyrazoline, and pyrimidine as possible inhibitors of the epidermal growth factor receptor (EGFR) kinase, AutoDock estimated the binding affinities of these derivatives and showed that the EGFR-kinase inhibitors derivatives of chalcone, pyrazoline, and pyrimidine exhibit strong binding energies., ranging from 10.91 to 7.32 kcal/mol. Compound 18, a pyrimidine derivative, has shown higher in vitro activity than compound 17, inhibiting EGFR kinase even at low doses of 0.19 lM.³⁷

17 18

Al-Warhi et.al. synthesized novel series of thiazolyl-pyrazoline derivatives and were evaluated for in vitro antitumor action using the MTT assay against the breast cancer cell line T-47D and the lung cancer cell line A549. Specifically, the most effective thiazolyl pyrazolines were 19 and 20, which had IC₅₀ values of 3.92 and 6.53 µM against A549 cells and 0.88 and 0.75 µM against T-47D cells, respectively.³⁸

19 20

Fakhry et al hybridized thiazole and pyrazoline fragments served as the basis for the invention of a novel family of EGFR/HER2 dual inhibitors by. The synthesized compounds 21 and 22 shown significant anti-proliferation against MCF-7, with corresponding IC₅₀values of 7.21 and 8.02 µM. At IC₅₀ values of 0.013 and 0.027 µM, respectively, compounds 21 and 22 demonstrated strong inhibitory action for HER2, and EGFR at 0.009 and 0.051 µM. ³⁹

21 22

Mustofa et al. synthesized N-phenyl pyrazoline compounds 23 and 24 having IC₅₀ 26 µM and 4.708 µM, respectively, illustrate cytotoxicity in the HeLa cell line. More studies show that N-phenyl pyrazoline 24 reduces the migratory and proliferation potential of the HeLa cell line in a dose-dependent fashion. N-phenyl pyrazoline 24 diminishes the degree of EGFR expression, however it does not completely inhibit ERK1/2. ⁴⁰

23 24

Al-Wahaibi et al. created novel bis-pyrazoline hybrids with dual EGFR and BRAFV600E inhibitors, which were tested against four cancer cell lines in vitro. Strong antiproliferative effects were shown by compounds 25and 26 whose GI₅₀values were 1.05 µM, 1.50 µM, and 1.20 µM, respectively. In hybrids, there was parallel inhibition of BRAFV600E and EGFR. Compounds 25and 26 indicated encouraging anticancer potential and inhibited EGFR-like erlotinib. ⁴¹

Al-Wahaibi et al. created several unique 3-cyanopyridone/pyrazoline hybrids that show dual inhibition against BRAFV600E and EGFR. With GI₅₀ values of 25 nM and 27 nM, respectively, compounds 27 and 28 showed strong antiproliferative activity. The EGFR and BRAFV600E pathways were both dualy inhibited by these hybrids. Compound 28 was determined to be the most potent inhibitor against BRAFV600E and the growth of cancer cells. ⁴²

Fakhry et al. synthesized a new family of thiazolyl-pyrazoline derivatives Compounds 29, 30 and 31 showed strong anticancer effect against MCF-7 with IC50 values of 4.08, 5.64, 3.37, and 3.54 µM, respectively, in contrast to lapatinib, which had an IC₅₀ of 5.88 µM. Enzymatic tests were also carried out to provide additional evidence of the dual inhibitory action of the most cytotoxic medications (30 and 31) against EGFR and HER2. They demonstrated encouraging inhibitory activity against HER2 having IC₅₀ = 0.047 and 0.022 µM and EGFR having IC₅₀ value 0.024 and 0.005 µM, respectively, as compared to lapatinib having IC₅₀ = 0.007 and 0.018 µM. ⁴³

29 30

Nattava et.al. had synthesized a novel series of compounds by Claisen-Schmidt condensation, schiff’s base and cyclization mechanism. Compared to the standard Diclofenac's 94.2%, compound 32 showed the highest percentage of inhibition of all the compounds, measuring 98.4%.Compound 32 had the lowest IC₅₀at a dosage of 20.01µg against MCF7 cell lines and 32.87µg against SKOV3 cell lines. ⁴⁴

Rana et.al. designed and synthesized N-formyl/acetyl 1,3,5-trisubstituted pyrazoline analogs, pyrazole-based chalcones, and pyrazole analogs . Analog 33 has the most anticancer activity of all the substances against A549 having IC₅₀ = 37.59 mM and HeLa having IC₅₀ = 23.6 mM. ⁴⁵

Chunaifah et al. synthesized and assessed the anticancer potential of N-phenyl pyrazoline derivatives based on thiophene that have methoxy groups utilizing both in vitro and in silico experiments. Among the synthesized pyrazolines, compound 34 shown to be the most potent anticancer drug; against the 4T1, HeLa, and WiDr cancer cell lines, it showed IC₅₀ values of 9.09, 9.27, and 0.25 µg/ml, respectively. In silico analysis utilizing molecular docking against the EGFR suggest that compound 34 the least amount of binding energy, 8.8 kcal/mol, which was consistent with the experimental findings.⁴⁶

CONCLUSION:

The literature reports on anticancer pyrazoline hybrids that are less susceptible to drug resistance were compiled into this review. Several scientists have chosen to construct these kinds of compounds because pyrazolines are adaptable compound with strong anticancer properties. A substitution for the pyrazoline ring modifies the inhibitory action of EGFR.

CONFLICT OF INTEREST:

No conflicts of interest are disclosed by the author.

ACKNOWLEDGMENTS:

The researchers express their gratitude to Rashtrasant Tukadoji Maharaj Nagpur University Nagpur, Department of Pharmaceutical Sciences for their support of this research.

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Received on 19.08.2024 Revised on 12.12.2024

Accepted on 07.03.2025 Published on 01.10.2025

Available online from October 04, 2025

Research J. Pharmacy and Technology. 2025;18(10):5081-5088.

DOI: 10.52711/0974-360X.2025.00734

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