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Article

Synthesis, Antioxidant and Antiproliferative Actions of 4-(1,2,3-Triazol-1-yl)quinolin-2(1H)-ones as Multi-Target Inhibitors

by
Essmat M. El-Sheref
1,*,
Stefan Bräse
2,*,
Hendawy N. Tawfeek
1,3,
Fatmah Ali Alasmary
4 and
Bahaa G. M. Youssif
5
1
Chemistry Department, Faculty of Science, Minia University, El-Minia 61519, Egypt
2
Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
3
Unit of Occupational of Safety and Health, Administration Office of Minia University, El-Minia 61519, Egypt
4
Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
5
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(17), 13300; https://doi.org/10.3390/ijms241713300
Submission received: 19 July 2023 / Revised: 19 August 2023 / Accepted: 25 August 2023 / Published: 27 August 2023
(This article belongs to the Special Issue Cyclic and Heterocyclic Compounds in Drug Synthesis and Delivery)
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Versions Notes

Abstract

:
The reaction of 4-azido-quinolin-2(1H)-ones 1a–e with the active methylene compounds pentane-2,4-dione (2a), 1,3-diphenylpropane-1,3-dione (2b), and K2CO3 was investigated in this study. This approach afforded 4-(1,2,3-triazol-1-yl)quinolin-2(1H)-ones 3a–j in high yields and purity. All newly synthesized products’ structures were identified. Compounds 3a–j were tested for antiproliferative activity against a panel of four cancer cell lines. In comparison to the reference erlotinib (GI50 = 33), compounds 3f–j were the most potent derivatives, with GI50 values ranging from 22 nM to 31 nM. The most effective antiproliferative derivatives, 3f–j, were subsequently investigated as possible multi-target inhibitors of EGFR, BRAFV600E, and EGFRT790M. Compound 3h was the most potent inhibitor of the studied molecular targets, with IC50 values of 57 nM, 68 nM, and 9.70 nM, respectively. The apoptotic assay results demonstrated that compounds 3g and 3h function as caspase-3, 8, and Bax activators as well as down-regulators of the antiapoptotic Bcl2, and hence can be classified as apoptotic inducers. Finally, compounds 3g and 3h displayed promising antioxidant activity at 10 µM, with DPPH radical scavenging of 70.6% and 73.5%, respectively, compared to Trolox (77.6%).

1. Introduction

Despite scientific and social advancements, cancer remains one of the most prevalent diseases of concern and a primary cause of human suffering. Cancer deaths globally are expected to climb by more than 13.1 million by 2030, according to estimates [1,2,3,4]. As a result, the development of newer and more potent anticancer treatments with stronger selectivity on neoplastic cells and fewer side effects, capable of overcoming challenges such as extreme toxicity and resistance to existing drugs, may be contemplated [5,6,7]. The potential that some compounds with antioxidant properties can explain chemopreventive action is a matter of ongoing discussion. Indeed, numerous previous studies have found that antioxidants can improve existing chemotherapy protocols by reducing hazardous side effects while maintaining treatment efficacy [8,9,10]. Furthermore, further in vitro studies suggest that these compounds play an important role in causing apoptosis in cancer cells [11,12].
Cancer is a term used to describe a group of diseases caused by abnormalities in cell proliferation and replication [13]. Cancer cells typically have a large number of mutations; no two samples from the same patient are same [14,15,16]. As a result, only medications that act on many cancer-related pathways at the same time can achieve improved drug efficacy and minimize the risk of drug resistance. Multi-targeted medications have long been used in the clinic in the forms of both “Cocktail Therapy” [17,18], which combines numerous drugs, and “multi-component drugs” [19,20], which combine two or more drugs in a single tablet. A combination of targeted medicines has been authorized as an effective strategy to cure cancer. A pharmacogenomic platform was developed for the quick identification of drug combinations that can overcome resistance in specific individuals [21,22].
Although these strategies can achieve poly-pharmacological effects, they have encountered unavoidable challenges, such as the difficulty and length of time required to determine the best therapeutic pairings and timing, the difficulty in managing the bio-distribution characteristics and pharmacokinetics of a particular treatment, potential interactions between several drugs that lead to potential side effects, and low patient tolerance [23,24]. Alternatively, the development of a single chemical entity containing a pharmacological combination that works on many cancer-relevant sites could potentially overcome these issues. These anticancer drugs, known as “single molecule multiple targets”, “multiple ligands”, or “hybrids”, have received a lot of interest in recent years [25,26,27,28,29]. Multiple ligands provide certain distinct advantages over cocktail and multi-component medications, including reduced risk of drug interactions, simplified drug metabolism, enhanced drug transport, and lower drug research and development expenses. These characteristics make them promising candidates for the development of the next generation of anticancer medicines. In reality, some medications currently in clinical trials target many ligands, while this was not their intention at the outset. For example, the FDA-approved kinase inhibitors sorafenib [30] and sunitinib [31], which are utilized in the clinic for cancer therapy, target different types of kinases.
Several antineoplastic drugs with various structures have been developed as a consequence of research efforts over the last few decades [32,33]. Due to its biodiversity and plasticity, the quinoline nucleus has been a highly favored motif for the target-based design and development of anticancer agents [34]. Quinolone derivatives, on the other hand, have an important place in medicinal chemistry due to their distinct structure and recognized therapeutic impact; whether natural or synthetic, they have demonstrated a wide range of pharmacological actions [35,36], with a promising role in the improvement of anti-cancer drug resistance [37,38,39]. Furthermore, several quinolones have been discovered to have great effects in a variety of operations, including growth inhibition by cell cycle arrest, apoptosis, and angiogenesis inhibition [40,41,42].
Moreover, small compounds, such as quinazoline derivatives, can suppress EGFR by inhibiting tyrosine kinase at ATP-binding sites [43,44]. The FDA has approved afatinib, gefitinib, and erlotinib (Figure 1), quinazoline derivatives designed to block EGFR kinase, for the treatment of non-small-cell lung and breast cancers [45,46]. The bioisosteric replacement of the quinazoline ring system with quinoline resulted in quinoline derivatives such as neratinib and pelitinib (Figure 1), which are potent EGFR kinase inhibitors [47,48]. Many researchers were encouraged by the above-mentioned results to design and synthesize a series of quinoline-based EGFR inhibitors, which are expected to be as potent as structurally related quinazoline bioisosteres.
In a recent publication [34], we described the design, synthesis, and antiproliferative activity of a novel class of quinoline-based compounds as possible dual inhibitors of EGFR and BRAFV600E. Compound I (Figure 2) was the most effective derivative, with a GI50 value of 3.30 µM against four cancer cell lines, when compared to the reference doxorubicin (GI50 = 1.13 µM). Compound I inhibited both EGFR and BRAFV600E with IC50 values of 1.30 µM and 3.80 µM, respectively. Another study [49] described the development of a novel set of quinoline-based compounds as possible multi-target antiproliferative agents. Compound II (Figure 2) was proven to be the most potent derivative, with a GI50 value of 1.05 µM against the four cancer cell lines examined, when compared to doxorubicin (GI50 = 1.10 µM). Compound II demonstrated the best topo II inhibitory activity at the examined concentrations (100 µM = 47.6% and 20 µM = 19.5%) when compared to the positive control, etoposide (100 µM = 83.7% and 20 µM = 66.0%). Moreover, compound II exhibited promising dual inhibitory action against CDK2 and EGFR with IC50 values of 1.60 µM and 0.40 µM, respectively.
Additionally, 1,2,3-triazoles have found substantial uses in pharmaceutical chemistry [50,51,52,53] due to their ease of synthesis, and the click procedure was the best and most common way to synthesize 1,2,3-triazole ring via copper(I)-catalyzed azide–alkyne cycloaddition [54,55,56,57]. Because of their potential biological actions, scientific attention is now focused on the synthesis of 1,4- and 1,5-disubstituted 1,2,3-triazoles [52,58].
Motivated by these findings, and in the pursuit of a new antiproliferative agent with potential multi-target inhibitory action [27,28,29,59,60,61,62], we present here the design, synthesis, and antiproliferative activity of a new series of quinoline/1,2,3-triazole hybrids 3a–j (Figure 2) as potential multi-target inhibitors.
Compounds 3a–j were evaluated for cell viability against a normal human cell line (human mammary gland epithelial (MCF-10A) cell line). All of the newly synthesized analogues were tested for antiproliferative activity against four cancer cell lines. The most potent derivatives were studied further as multi-target inhibitors against wild-type EGFR, mutant-type EGFR (EGFRT790M), and BRAFV600E. The most active derivative’s potential apoptotic and antioxidant capabilities were also examined.

2. Results and Discussion

2.1. Chemistry

Previously, our research team has identified numerous quinolone derivatives with a 1,2,3-triazole ring. In addition, in recent publications, we described an effective methodology for the synthesis of 4-(1,2,3-triazol-2-yl)quninolin-2-ones via the click reaction and investigated their biological characteristics [63,64]. However, in this study, we synthesize analogous 1,2,3-triazoloquinolone derivatives by reacting 4-azido-2-quinolinones 1a–e with active methylene compounds such as pentane-2,4-dione (2a) and 1,3-diphenylpropane-1,3-dione (2b) (Scheme 1).
To optimize the reaction condition, we performed the reaction by starting with 4-azidoquinolin-2(1H)-one (1a) and pentane-2,4-dione (2a) as active methylene compounds and various bases at room temperature, worming, and under refluxing temperature. When we employed other bases to optimize our conditions, such as Et3N, piperidin, NaOH, and KOH in ethanol as a solvent, we obtained compound 3a with a negligible yield of less than 20% when either cold or hot (Table 1). By contrast, in the presence of inorganic bases, namely K2CO3 in ethanol, product 3a was obtained in excellent yields of 90%. By performing the reaction under the above optimizing conditions with 1,3-diphenylpropane-1,3-dione (2b), we obtained the product 3f in an excellent yield as 82%. So, the best result was obtained when the reaction was conducted by starting with 4-azidoquinolin-2(1H)-one 1a–e (1 mmol), the active methylene compounds 2a,b (1 mmol), and 1.2 mmol of K2CO3 in ethanol according to a previous publication [65].
The structures for all obtained products are fully consistent with their spectral data, such as 1H NMR, 13C NMR spectrum, mass spectrometry, and elemental analysis. To confirm our results, we choose compound 3b, which was assigned as 4-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-6-methylquinolin-2(1H)-one (Figure 1). Mass spectrometry and elemental analysis for compound 3b indicate that it has the molecular formula of C15H14N4O2 with m/z 282, which indicate that it is the result of a combination between one molecule of 4-azido-6-methylquinolin-2(1H)-ones (1b) and one molecule of acetyl acetone (2a) with the elimination of one molecule of H2O. The 1H NMR spectra for compound 3b showed five singlet signals in a ratio (1:1:3:3:3) with chemical shifts at δH 12.26, 7.40, 6.87, 3.32, 2.45, and 2.26 ppm, which were assigned as NH, H-5, COCH3, CH3 (H-5a’), and CH3 (H-6a), respectively. The three methyl groups were further confirmed from their 13C NMR spectra, which gave signals at δC 27.67 (COCH3), 20.38 (CH3-6a), and 9.29 ppm (CH3-5a’).
Also, the 13C NMR spectra clearly showed the presence of two downfield signals at δC 193.14 and 160.76 ppm, which were assigned as (COCH3) and quniolinone-C-2, respectively, as shown in Figure 3. All spectral signals that appeared in 1H NMR spectra or in 13C NMR spectra were identical to those in mass spectrometry and elemental analysis, and to the structure, which was deduced exactly.
Furthermore, in all obtained products 3a–j, the elemental analysis and mass spectrometry clearly show that the gross formula for all compounds came from the reaction between one mole of 4-azidoquinolin-2(1H)-ones (1a–e) and one mole of the active methylene (2a,b) with the elimination of one H2O molecule. Also, the 1H NMR clearly showed the presence of a downfield singlet signal at δH = 6.86–6.96 ppm, which was assigned as quinolinon-H-3 and confirmed with 13C NMR with a chemical shift at δC = 120.38–122.24 ppm for all obtained products. Additionally, the presence of two carbonyl groups was confirmed by the 13C NMR with a chemical shift at δC = 160.20–160.97, 186.08–186.18, and 193.09–193.18 ppm, for all quinolinon-C-2 (for compounds 3a–j), COCH3 (for compounds 3a–e), and COPh (compounds 3f–j), respectively.
Finally, through the chemical shift’s value of the external carbonyl group COR as shown above, which refers to the nature of the group attached to the carbonyl, as the methyl group is a donor group and the phenyl group is withdrawn, the first appears at a lower value in the 13C NMR spectroscopy. Through the preceding values of the different analyses, the validity of the chemical composition of all the compounds that were obtained is clear, and it is clear that the behavior of the 4-azidoquinoli-2(1H)-ones 1a–e with the active methylene 2a,b, whether aromatic or aliphatic, exhibited the same behavior during the reaction as shown in Scheme 1.
The formation of compounds 3a–j can be rationalized with the following suggested mechanism (Scheme 2) via the two steps shown below. The first step included the formation of active methylene via abstracting a hydrogen proton from 2a,b by K2CO3. The second step involved 1,3-dipolar cycloaddition of the enolate 2− on the N3-group of the 4-azidoquinolin-2(1H)-ones 1a–e and forming the intermediate 4, and then intra-nucleophilic addition from the N-3 atom of the 1a–e on the carbonyl group and cyclization resulting in the adduct 5 which accepted a hydrogen proton and the loss of a H2O molecule to give the final products 3a–j.

2.2. Biochemical Assays

2.2.1. Cell Viability Assay

The human mammary gland epithelial (MCF-10A) cell line was used to investigate the viability of the 1,2,3-triazole-based derivatives 3a–j. Compounds 3a–j were cultured on MCF-10A cells for four days before being evaluated for vitality using the MTT assay [66,67]. According to Table 1, none of the compounds examined displayed cytotoxic effects, and the cell viability for the compounds tested at 50 µM was greater than 87%.

2.2.2. Antiproliferative Assay

The antiproliferative activity of 3a–j was evaluated against four human cancer cell lines using the MTT assay [49,68] and erlotinib as the reference drug: Panc-1 (pancreatic cancer cell line), MCF-7 (breast cancer cell line), HT-29 (colon cancer cell line), and A-549 (human epithelial cancer cell line). Table 2 displays the median inhibitory concentration (IC50) and the average of IC50 (GI50).
In general, compounds 3a–j had promising antiproliferative activity, with GI50 against the four cancer cell lines tested ranging from 22 nM to 65 nM, compared to erlotinib’s 33 nM. The newly synthesized compounds 3a–j can be divided into two major Scaffolds. Scaffold A compounds are 4-acetly, 5-methyl-1,2,3-triazoles 3a–e (R4 = CH3), and scaffold B compounds are 4-benzoyl, 5-phenyl-1,2,3-triazoles 3f–j (R4 = Ph). Compounds 3a–e (R4 = CH3) showed GI50 values ranging from 39 nM to 65 nM and were found to be less potent than congeners 3f–j (R4 = Ph) of GI50 values ranging from 22 nM to 31 nM, indicating the relevance of the phenyl group of 1,2,3-triazole moiety for the antiproliferative action.
Compounds 3f, 3g, 3h, and 3i (Scaffold B) were revealed to be the most potent derivatives, with GI50 values of 28, 26, 22, and 31 nM, respectively. These compounds outperformed the reference drug erlotinib (GI50 = 33 nM). Compounds 3f, 3g, and 3h were found to be more effective than erlotinib against all cancer cell lines tested.
Compound 3h (R1 = R3 = H, R2 = OCH3, R4 = Ph) was the most potent derivative among all synthesized derivatives, with a GI50 value of 22 nM, 1.5-fold more potent than the reference erlotinib. The phenyl ring substitution on the 1,2,3-triazole moiety results in compound 3c (R1 = R3 = H, R2 = OCH3, R4 = CH3), which had a GI50 value of 39 nM and was 1.8-fold less potent than compound 3h, indicating the relevance of the phenyl ring substitution on the 1,2,3-triazole moiety.
Another significant point to consider is the relevance of the substitution pattern at position five on the quinoline moiety, as seen in compounds 3g (R1 = R3 = H, R2 = CH3, R4 = Ph) and 3f (R1 = R3 = H, R2 = H, R4 = Ph). Compounds 3g and 3f have GI50 values of 26 nM and 28 nM, respectively, and are both less potent than 3h (R1 = R3 = H, R2 = OCH3, R4 = Ph), demonstrating the importance of the substitution pattern of position five of the quinoline moiety on the antiproliferative activity of the newly synthesized compounds and that the activity increases in the order OCH3 > CH3 > H. Additionally, compound 3i (R1 = CH3, R3 = H, R2 = H, R4 = Ph) had a GI50 value of 35 nM, which was less potent than compound 3f (R1 = R3 = H, R2 = H, R4 = Ph), suggesting the relevance of the quinoline moiety’s Free N-1 atom for antiproliferative action.
Finally, as stated above, Scaffold A compounds 3a–e (R4 = CH3) were less potent than compounds 3f–j (R4 = Ph), with GI50 values ranging from 39 nM to 65 nM, where all parameters that affect the activity of compounds 3f–j were also present in compounds 3a–e. For example, compound 3c (R1 = R3 = H, R2 = OCH3, R4 = CH3) had a GI50 value of 39 nM against the four cancer cell lines tested, being more potent than compounds 3b (R1 = R3 = H, R2 = CH3, R4 = Ph) and 3a (R1 = R3 = H, R2 = H, R4 = Ph), indicating the relevance of the methoxy group at the fifth position of the quinoline ring to antiproliferative action. Moreover, compound 3d (R1 = CH3, R3 = H, R2 = H, R4 = CH3) had a GI50 value of 62 nM, being 1.4-fold less potent than 3a, indicating the relevance of the quinoline moiety’s Free N-1 atom for antiproliferative action.

2.2.3. EGFR Inhibitory Assay

Compounds 3f, 3g, 3h, and 3j, the most effective antiproliferative derivatives, were evaluated for their inhibitory action on EGFR as a potential target for their antiproliferative action [69]. Table 3 and Figure 4 show the results as IC50 values versus erlotinib as a reference drug. The investigated compounds 3f, 3g, 3h, and 3j demonstrated promising EGFR inhibitory action with IC50 values of 72 nM, 64 nM, 57 nM, and 79 nM, respectively. The results of the EGFR inhibitory assay corroborate the results of the antiproliferative assay, with the most active antiproliferative derivatives also being the most active EGFR inhibitors, showing that EGFR may be a viable target for antiproliferative activity. Compounds 3f, 3g, and 3h demonstrated superior EGFR inhibitory action to the reference erlotinib, where compound 3j (IC50 = 79 nM) was equipotent to erlotinib (IC50 = 80 nM). The most potent antiproliferative agent, compound 3h, was also the most potent EGFR inhibitor, with an IC50 value of 57 nM, being 1.4-fold more potent than erlotinib.

2.2.4. BRAFV600E Inhibitory Assay

Compounds 3f, 3g, 3h, and 3j were tested for their ability to inhibit mutant BRAF [62]. Table 3 and Figure 4 display the results as IC50 values. With IC50 values ranging from 68 nM to 93 nM, the compounds examined showed potential inhibitory activity against BRAFV600E. In all cases, the investigated derivatives were shown to be less effective as BRAFV600E inhibitors than erlotinib (IC50 = 60 ± 5 nM). The most potent antiproliferative agent and EGFR inhibitor, compound 3h, was also the most potent BRAFV600E inhibitor, with an IC50 value of 68 ± 5 nM, comparable to erlotinib in BRAFV600E inhibitory action. Compounds 3f and 3g were shown to be the second and third most active, with IC50 values of 86 ± 6 nM and 73 ± 6 nM, respectively. Finally, compound 3j was the least effective BRAFV600E inhibitor, with an IC50 of 97 ± 7 nM, being 1.6-fold less potent than the reference erlotinib (IC50 = 60 ± 5 nM). Compounds 3g and 3h were discovered to be potential antiproliferative agents with dual EGFR and BRAFV600E inhibitory action, requiring significant structural modifications in their backbone structures to optimize their biological activity.

2.2.5. EGFRT790M Inhibitory Assay

Compounds 3g and 3h’s encouraging results as antiproliferative agents with potential EGFR and BRAFV600E inhibitory activities motivated us to test their efficacy on the mutant EGFR (EGFR T790M) receptor type [59]. Results were cited as IC50 values in Table 3 and Figure 4 against osimertinib as a reference drug. Compounds 3g and 3h inhibited EGFRT790M with IC50 values of 8.40 ± 0.7 nM and 9.70 ± 0.8 nM, which were equivalent to the reference Osimertinib’s IC50 value of 8 nM. These findings add to the evidence of the investigated compounds’ antiproliferative activity, which can serve as multi-target inhibitors.

2.2.6. Apoptotic Assays

Controlling or perhaps terminating the uncontrolled proliferation of cancer cells is one method of treating cancer. Using the cell’s natural dying process is a very successful strategy. Apoptosis evasion is a hallmark of cancer and is not particular to the cause or kind of cancer, and hence targeting apoptosis is useful for many types of cancer. Many anticancer medications target different phases in both the intrinsic and extrinsic pathways [70,71,72]. Compounds 3f, 3g, and 3h were tested for their capacity to activate the apoptosis cascade and disclose their proapoptotic potential.

Caspase-3 Assay

Caspases play a crucial function in the induction and achievement of apoptosis. Caspase-3 is an essential caspase that cleaves different proteins in cells, resulting in apoptosis [73,74]. The most potent derivatives in all in vitro studies, compounds 3f, 3g, and 3h, were tested as caspase-3 activators against the human epithelial cancer cell line (A-594) [29], and the findings are reported in Table 4. The results showed that compounds 3f, 3g, and 3h had promising caspase-3 protein overexpression levels of 524 ± 5, 587 ± 5, and 715 ± 6 pg/mL, respectively. They elevated the protein caspase-3 in the A-594 cancer cell line by approximately 8, 9, and 11 times when compared to untreated control cells. In all cases, the investigated compounds 3g, 3f, and 3h were shown to be more active than the standard staurosporine, which had a caspase-3 level overexpression of 465 ± 4 pg/mL. These findings demonstrated the investigated compounds’ apoptotic potential, which may explain their antiproliferative activity.

Caspase 8, Bax, and Bcl-2 Level Assays

Compounds 3g and 3h were investigated further for their effect on caspase-8, Bax, and antiapoptotic Bacl-2 levels against the human epithelial cancer cell line (A-594) using staurosporine as a control, as shown in Table 4. Compared to staurosporine, 3g and 3h noticeably increased caspase-8 and Bax levels.
Caspase-8 overexpression was highest in compound 3h (2.35 ng/mL), followed by 3g (2.17 ng/mL) and standard staurosporine (1.85 ng/mL). In comparison to the control untreated cells, 3g and 3h increased caspase-8 levels by 24-fold and 26-fold, respectively.
Moreover, when compared to untreated A-594 cancer cells, compounds 3g and 3h induced Bax 36- and 37-fold greater (315 pg/mL and 336 pg/mL, respectively) than staurosporine (288 pg/mL, a 32-fold induction). Finally, compared to staurosporine, compounds 3g and 3g elicited equipotent down-regulation of anti-apoptotic Bcl-2 protein levels in the A-594 cell line. These findings suggest that 3g and 3h function as caspase-3, 8, and Bax activators and down-regulators of the antiapoptotic Bcl2, and hence can be classified as apoptotic inducers.

2.2.7. Antioxidant Activity

Antioxidant compounds have assumed a key position in medicine because of their widespread preventive and therapeutic application in various disorders. Free radicals play an essential part in cancer, cardiovascular and auto-immune disorders, and aging-related problems, leading to new medical approaches [61]. The scavenging of stable free radicals by 2,2-diphenyl-1-picrylhydrazyl (DPPH) was used to investigate the potential antioxidant properties of compounds 3f, 3g, and 3h, using Trolox as a control (Table 5) [75].
The assay was carried out at three different concentrations of the investigated compounds (100 µM, 50 µM, and 10 µM). Compounds 3g and 3h displayed promising antioxidant activity at 10 µM, with DPPH radical scavenging of 70.6% and 73.5%, respectively, compared to Trolox (77.6%). Compounds 3g and 3h show comparable radical scavenging activity to Trolox at 100 and 50 µM, respectively (Table 4). Compound 3f was determined to be the least active compound regarding antioxidant activity. These findings indicated that compounds 3g and 3h could be regarded as potent antiproliferative agents with antioxidant action.

3. Materials and Methods

3.1. Chemistry

General information: refer to Additional information (Supplementary File Figures S1–S32)
Starting materials
4-azidoquinolin-2(1H)-ones 1a–e were prepared according to the published literature [76,77]. The active methylene compounds used were pentane-2,4-dione (2a) and 1,3-diphenylpropane-1,3-dione (2b), and they were used as purchased (Merck).
General procedure for the synthesis of 4-(1,2,3-triazol-1-yl)quinolin-2-ones (3a–j) [78,79]
In 30 mL of ethanol, we combined 4-azido-2-quinolinones 1a–e (1 mmol), active methylene ketones 2a, b (1.0 mmol), and K2CO3 (1.2 mmol). For 20 h, the reaction mixture was stirred at room temperature. Compounds 3a–j were obtained after the reaction was completed by pouring them into a 500 mL beaker containing 200 gm of crushed ice (in the case of the reaction with 2b) or by evaporating the solvent (in the case of the reaction with 2a). All of the obtained 3a–j products were recrystallized from ethanol.

3.1.1. 4-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (3a)

This compound was found to be a pale yellow solid; mp 243-45 °C; yield 90%; 1H NMR (DMSO-d6): δH 12.28 (s, 1H, NH), 7.63 (t, 1H, J = 7.5 Hz, H-7), 7.50 (d, 1H, J = 8.4 Hz, H-8), 7.18 (t, J = 7.8 Hz, 1H, H-6), 6.90 (d, 1H, J = 9.3 Hz, H-5), 6.89 (s, 1H, H-3), 3.32 (s, 3H, COCH3), 2.35 ppm (s, 3H, H-5a’); 13C NMR (DMSO-d6): δC 193.18 (CO), 160.97 (CO, C-2), 142.60 (C-4), 142.24 (C-5’), 139.39 (C-4’), 139.24 (C-7), 132.15 (C-5), 123.46 (C-8a), 121.26 (C-6), 120.68 (C-3), 115.98 (C-8), 115.57 (C-4a), 27.74 (CH3), 9.31 ppm (CH3); EI-MS: m/z 268 (M+, 17). Anal. Calcd for C14H12N4O2: C, 62.68; H, 4.51; N, 20.88. Found: C, 62.77; H, 4.39; N, 20.69.

3.1.2. 4-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-6-methylquinolin-2(1H)-one (3b)

This compound was found to be a pale yellow solid; mp 296-98 °C; yield 90%; 1H NMR (DMSO-d6): δH 12.26 (s, 1H, NH), 7.48 (d, 1H, J = 1.2 Hz, H-7), 7.45 (d, 1H, J = 0.9 Hz, H-8), 7.40 (s, 1H, H-5), 6.87 (s, 1H, H-3), 3.33 (s, 3H, COCH3), 2.67 (s, 3H, H-6a), 2.26 ppm (s, 3H, H-5a’); 13C NMR (DMSO-d6): δC 193.14 (CO), 160.76 (CO, C-2), 142.57 (C-4), 142.02 (C-5’), 139.16 (C-4’), 138.16 (C-7), 137.42 (C-5), 122.56 (C-8a), 121.14 (C-3), 115.91 (C-6), 115.49 (C-8), 27.67 (CH3), 20.38 (6-CH3), 9.29 ppm (CH3); EI-MS: m/z 282. Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.71; H, 5.12; N, 20.02.

3.1.3. 4-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-6-methoxyquinolin-2(1H)-one (3c)

This compound was found to be a colorless solid; mp 263-65 °C; yield 87%; 1H NMR (DMSO-d6): δH 12.25 (s, 1H, NH), 7.42 (s, 1H, H-5), 7.33 (d, 1H, J = 2.1 Hz, H-7), 7.30 (d, 1H, J = 2.1 Hz, H-8), 6.90 (s, 1H, H-3), 3.78 (s, 3H, OCH3), 3.33 (s, 3H, COCH3), 2.47 ppm (s, 3H, H-5a’); 13C NMR (DMSO-d6): δC 193.11 (CO), 160.40 (CO, C-2), 154.73 (C-6), 142.62 (C-4), 141.71 (C-5’), 139.16 (C-4’), 133.99 (C-5), 121.55 (C-8a), 121.17 (C-3), 117.48 (C-4a), 55.54 (OCH3), 27.66 (COCH3), 9.32 ppm (CH3); EI-MS: m/z 298 (M+, 35). Anal. Calcd for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78. Found: C, 60.51; H, 4.66; N, 18.91.

3.1.4. 4-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-8-methylquinolin-2(1H)-one (3d)

This compound was found to be a colorless solid; mp 255-57 °C; yield 71%; 1H NMR (DMSO-d6): δH 12.76 (s, 1H, NH), 7.79 (m, 1H, H-6), 7.25 (d, 2H, J = 1.2 Hz, H-5,7), 6.93 (s, 1H, H-3), 3.73 (s, 3H, COCH3), 3.45 (s, 3H, N-CH3), 2.45 ppm (s, 3H, H-5a’); 13C NMR (DMSO-d6): δC 193.12 (CO), 160.55 (CO, C-2), 142.49 (C-4), 141.12 (C-5’), 140.12 (C-4’), 139.60 (C-7), 137.49 (C-5), 123.41 (C-8a), 122.12 (C-6), 120.12 (C-3), 116.41 (C-8), 115.12 (C-4a), 27.64 (CH3), 20.31 (N-CH3), 9.28 ppm (CH3); EI-MS: m/z 282. Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.70; H, 4.87; N, 19.96.

3.1.5. 4-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-1-methylquinolin-2(1H)-one (3e)

This compound was found to be a pale yellow solid; mp 188-90 °C; yield 88%; 1H NMR (DMSO-d6): δH 7.74 (m, 2H, H-6,7), 7.29 (d, 1H, J = 6.6 Hz, H-5), 7.25 (d, J = 1.2 Hz, 1H, H-8), 6.93 (s, 1H, H-3), 3.72 (s, 3H, N-CH3), 3.34 (s, 3H, COCH3), 2.45 ppm (s, 3H, H-5a’); 13C NMR (DMSO-d6): δC 193.09 (CO), 160.20 (CO, C-2), 142.56 (C-4), 141.12 (C-5’), 140.12 (C-4’), 139.33 (C-7), 132.49 (C-5), 123.95 (C-8a), 122.91 (C-6), 120.38 (C-3), 116.41 (C-8), 115.60 (C-4a), 29.65 (N-CH3), 27.64 (COCH3), 9.22 ppm (CH3-5a’); EI-MS: m/z 282. Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.69; H, 5.13; N, 20.01.

3.1.6. 4-(4-Benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (3f)

This compound was found to be a pale yellow solid; mp 250-52 °C; yield 82%; 1H NMR (DMSO-d6): δH 12.22 (s, 1H, NH), 8.20-8.17 (m, 2H, Ar-H), 7.71-7.66 (t, 2H, J = 6.3 Hz, Ar-H), 7.59-7.55 (t, J = 7.8 Hz, 3H, Ar-H), 7.45-7.42 (m, 2H, Ar-H), 7.36-7.32 (m, 3H, Ar-H), 7.16-7.13 (m, 2H, Ar-H), 6.96 ppm (s, 1H, H-3); 13C NMR (DMSO-d6): δC 186.18 (CO), 160.70 (C-2), 143.04 (C-4), 142.65 (C-4’), 142.65, 142.58 (Ph-C), 138.96 (C-5’), 136.88 (C-7), 133.38 (C-6), 132.13 (C-5), 130.27, 130.07, 129.72, 128.41, 128.32, 125.19 (Ar-CH), 123.63 (C-8a), 122.24 (C-3), 115.82 (C-8), 115.64 ppm (C-4a); EI-MS: m/z 392 (M+). Anal. Calcd for C24H16N4O2: C, 73.46; H, 4.11; N, 14.28. Found: C, 73.55; H, 4.17; N, 14.14.

3.1.7. 4-(4-Benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl)-6-methylquinolin-2(1H)-one (3g)

This compound was found to be a pale yellow solid; mp 278-80 °C; yield 85%; 1H NMR (DMSO-d6): δH 12.21 (s, 1H, NH), 8.21-8.18 (d, J = 8.1 Hz, 2H, Ar-H), 7.71-7.67 (t, J = 7.2 Hz, 2H, Ar-H), 7.60-7.55 (t, J = 7.5 Hz, 2H, Ar-H), 7.44-7.30 (t, J = 6.3 Hz, 3H, Ar-H), 7.35-7.28 (m, 3H, Ar-H), 6.94 (s, 1H, H-5), 6.86 (s, 1H, H-3), 2.26 ppm (s, 3H, CH3); 13C NMR (DMSO-d6): δC 186.08 (CO), 160.52 (C-2), 142.70 (C-4), 142.58 (C-4’), 137.03, 136.89 (Ph-C), 133.43 (C-7), 133.32 (C-5), 132.13 (C-7), 130.24 (C-6), 130.01, 129.70, 128.39, 128.24, 125.33 (Ar-CH), 122.84 (C-8a), 121.99 (C-3), 115.73 (C-8), 115.48 (C-4a), 20.33 ppm (CH3); EI-MS: m/z 406 (M+, 5). Anal. Calcd for C25H18N4O2: C, 73.88; H, 4.46; N, 13.78. Found: C, 74.03; H, 4.61; N, 13.90.

3.1.8. 4-(4-Benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl)-6-methoxyquinolin-2(1H)-one (3h)

This compound was found to be a colorless solid; mp 290-92 °C; yield 87%; 1H NMR (DMSO-d6): δH 12.18 (s, 1H, NH), 8.17-8.14 (d, J = 7.5 Hz, 2H, Ar-H), 7.71-7.66 (t, J = 7.5 Hz, 2H, Ar-H), 7.59-7.54 (t, J = 7.5 Hz, 2H, Ar-H), 7.44-7.42 (d, J = 7.2 Hz, 2H, Ar-H), 7.36-7.34 (d, J = 4.8 Hz, 4H, Ar-H), 7.23 (s, 1H, Ar-H), 6.89 (s, 1H, H-3), 3.89 ppm (s, 3H, OCH3); 13C NMR (DMSO-d6): δC 186.44 (CO), 160.46 (C-2), 154.87 (C-6), 142.73 (C-4), 137.06, 133.72 (Ph-C), (C-4’), 137.03, 136.89 (Ph-C), 133.43 (C-7), 133.32 (C-5), 132.13 (C-7), 130.45 (C-6), 130.35, 129.90, 128.61, 128.56, 125.33 (Ar-CH), 122.84 (C-8a), 121.70 (C-3), 117.84 (C-8), 116.18 (C-4a), 55.80 ppm (OCH3). EI-MS: m/z 422 (M+). Anal. Calcd for C25H18N4O3: C, 71.08; H, 4.29; N, 13.26. Found: C, 71.19; H, 4.13; N, 13.41.

3.1.9. 4-(4-Benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl)-8-methylquinolin-2(1H)-one (3i)

This compound was found to be a colorless solid; mp 276-78 °C; yield 77%; 1H NMR (DMSO-d6): δH 11.38 (s, 1H, NH), 8.20-7.01 (m, 13H, Ar-H), 6.96 (s, 1H, H-3), 3.35 ppm (s, 3H, CH3); 13C NMR (DMSO-d6): δC 186.14 (CO), 161.05 (CO, C-2), 143.48 (C-4), 142.61 (C-5’), 137.36, 136.87 (Ph-C), 133.35 (C-4’), 130.23 (C-8a), 130.04, 129.70, 128.38, 128.29, 125.18 (Ar-CH), 124.41 (C-5), 122.56 (C-8), 122.02 (C-6), 121.48 (C-3), 115.88 (C-4a), 17.41 ppm (CH3); EI-MS: m/z 406 (M+). Anal. Calcd for C25H18N4O2: C, 73.88; H, 4.46; N, 13.78. Found: C, 73.69; H, 4.55; N, 13.60.

3.1.10. 4-(4-Benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl)-1-methylquinolin-2(1H)-one (3j)

This compound was found to be a pale yellow solid; mp 227-29 °C; yield 80%; 1H NMR (DMSO-d6): δH 8.20-8.18 (d, J = 8.1 Hz, 1H, Ar-H), 7.75-7.06 (m, 14H, Ar-H), 6.77 (s, 1H, H-3), 3.65 ppm (s, 1H, N-CH3); 13C NMR (DMSO-d6): δC 186.13 (CO), 159.95 (C-2), 142.74 (C-4), 142.62 (C-4′), 141.91, 141.58 (Ph-C), 139.70 (C-5′), 138.48 (C-7), 133.38 (C-6), 132.51 (C-5), 130.25, 130.10, 129.70, 128.99, 128.87, 126.36 (Ar-CH), 124.21 (C-8a), 122.96 (C-3), 116.48 (C-8), 115.54 (C-4a), 29.55 N-CH3); EI-MS: m/z 406 (M+). Anal. Calcd for C25H18N4O2: C, 73.88; H, 4.46; N, 13.78. Found: C, 73.72; H, 4.61; N, 13.66.

3.2. Biochemical Assays

3.2.1. Cell Viability Assay

The human mammary gland epithelial (MCF-10A) cell line was applied to assess the viability of the new derivatives 3a–j [66,67]. Refer to Additional information (Supplementary File).

3.2.2. Antiproliferative Assay

The MTT assay was used to compare the antiproliferative activity of 3a–j to four human cancer cell lines: colon cancer (HT-29) cell line, pancreatic cancer (Panc-1) cell line, lung cancer (A-549) cell line, and breast cancer (MCF-7) cell line, against erlotinib as the reference [68]. Refer to Additional information (Supplementary File).

3.2.3. EGFR Inhibitory Assay

Compounds 3f, 3g, 3h, and 3j, the most effective antiproliferative derivatives, were evaluated for their inhibitory action on EGFR as a potential target for their antiproliferative action [69]. Refer to Additional information (Supplementary File).

3.2.4. BRAFV600E Inhibitory Assay

Compounds 3f, 3g, 3h, and 3j were tested for their ability to inhibit mutant BRAF (BRAFV600E) according to reported procedures [62]. Refer to Additional information (Supplementary File).

3.2.5. EGFRT790M Inhibitory Assay

Compounds 3g and 3h were tested for their efficacy on the mutant EGFR (EGFR T790M) receptor type using the previously reported method [59]. Refer to Additional information (Supplementary File).

3.2.6. Apoptosis Assay

Caspase-3 Assay

The most potent derivatives in all in vitro studies, compounds 3f, 3g, and 3h, were tested as caspase-3 activators against human epithelial cancer cell line (A-594) [29]. See Additional information (Supplementary File).

Caspase 8, Bax, and Bcl-2 Level Assays

Compounds 3g and 3h were investigated further for their effect on caspase-8, Bax, and antiapoptotic Bacl-2 levels against the human epithelial cancer cell line (A-594) using staurosporine as a control [29]. See Additional information (Supplementary File).

3.2.7. Antioxidant Activity

The scavenging of stable free radicals by 2,2-diphenyl-1-picrylhydrazyl (DPPH) was used to investigate the potential antioxidant properties of compounds 3f, 3g, and 3h, using Trolox as a control [75]. See Additional information (Supplementary File).

4. Conclusions

Through a 1,3-dipolar cycloaddition approach, a novel series of 4-(1,2,3-triazol-1-yl)quinolin-2(1H)-ones (3a–j) was developed and synthesized in high yields and purity. The structures of all newly synthesized compounds were determined using elemental analysis, mass spectrometry, and NMR spectroscopy. The newly synthesized 3a–j showed potential antiproliferative efficacy against a panel of four cancer cell lines with compounds 3f–j being the most effective antiproliferative agents. Compounds 3f, 3g, 3h, and 3j were explored as possible multi-target inhibitors of EGFR, BRAFV600E, and EGFRT790M. Our findings demonstrated that compounds 3g and 3h can act as multi-target inhibitors. Furthermore, the apoptotic activity of compounds 3f, 3g, and 3h demonstrated that 3g and 3h activate caspase-3, 8, and Bax, as well as down-regulate the antiapoptotic Bcl2, and therefore can be classed as apoptotic inducers. Finally, DPPH radical scavenging activity demonstrated that compounds 3g and 3h are potent antiproliferative agents with promising antioxidant activity. After structural modifications, these newly synthesized compounds could constitute a new class of antiproliferative agents with multi-target inhibitory action.

Supplementary Materials

The supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms241713300/s1.

Author Contributions

Conceptualization, E.M.E.-S. and B.G.M.Y.; Methodology, E.M.E.-S. and B.G.M.Y.; Software, B.G.M.Y.; Writing—original draft, H.N.T., B.G.M.Y. and S.B.; Writing—review & editing, E.M.E.-S., S.B. and B.G.M.Y.; Funding acquisition, F.A.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The data will be available upon request.

Acknowledgments

The authors acknowledge support by the Researchers Supporting Project Number (RSP2023R259) King Saud University, Riyadh, Saudi Arabia. The authors also acknowledge support from the KIT-Publication Fund of the Karlsruhe Institute of Technology.

Conflicts of Interest

The authors report no potential conflict of interest.

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Ijms 24 13300 g001
Figure 1. Structures of some reported EGFR inhibitors.
Figure 1. Structures of some reported EGFR inhibitors.
Ijms 24 13300 g001
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Figure 2. Structures of compounds I and II and newly synthesized 3a–j.
Figure 2. Structures of compounds I and II and newly synthesized 3a–j.
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Scheme 1. Synthesis of 4-(1,2,3-triazol-1-yl)quinolin-2-ones (3a–j).
Scheme 1. Synthesis of 4-(1,2,3-triazol-1-yl)quinolin-2-ones (3a–j).
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Figure 3. The structure elucidation for compound 3b.
Figure 3. The structure elucidation for compound 3b.
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Scheme 2. Suggested mechanism for the formation of compounds 3a–j.
Scheme 2. Suggested mechanism for the formation of compounds 3a–j.
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Figure 4. IC50 of compounds 3f, 3g, 3h, and 3j against EGFR, EGFRT790M, and BRAFV600E.
Figure 4. IC50 of compounds 3f, 3g, 3h, and 3j against EGFR, EGFRT790M, and BRAFV600E.
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Table 1. Optimization conditions.
Table 1. Optimization conditions.
BaseEt3NNaOHKOHK2CO3T
3a15182092%r.t/st
3f11131982%
Table 2. Antiproliferative action of compounds 3a–j.
Table 2. Antiproliferative action of compounds 3a–j.
Compd.Cell Viability %Antiproliferative Activity IC50 ± SEM (nM)
A-549MCF-7Panc-1HT-29Average (GI50)
3a9045 ± 448 ± 446 ± 446 ± 446
3b9364 ± 668 ± 665 ± 664 ± 665
3c8938 ± 341 ± 438 ± 339 ± 339
3d9460 ± 665 ± 662 ± 662 ± 662
3e8754 ± 558 ± 556 ± 458 ± 557
3f9227 ± 230 ± 327 ± 228 ± 228
3g8924 ± 228 ± 226 ± 226 ± 226
3h9321 ± 224 ± 322 ± 222 ± 222
3i9132 ± 338 ± 335 ± 335 ± 335
3j9028 ± 234 ± 330 ± 330 ± 331
ErlotinibND30 ± 340 ± 330 ± 330 ± 333
ND: Not Determined.
Table 3. IC50 of compounds 3f, 3g, 3h, and 3j against EGFR, BRAFV600E, and EGFR790M.
Table 3. IC50 of compounds 3f, 3g, 3h, and 3j against EGFR, BRAFV600E, and EGFR790M.
Compd.EGFR Inhibition IC50 ± SEM (nM)BRAFV600E Inhibition IC50 ± SEM (nM)EGFRT790M Inhibition IC50 ± SEM (nM)
3f72 ± 686 ± 6ND
3g64 ± 573 ± 69.70 ± 0.80
3h57 ± 468 ± 58.40 ± 0.70
3j79 ± 697 ± 7ND
Erlotinib80 ± 560 ± 5ND
OsimertinibNDND8.00 ± 0.70
ND: Not Determined.
Table 4. Caspse-3, caspase-8, Bax, and Bcl-2 levels for compounds 3f, 3g, 3h, and Staurosporine on human epithelial cancer cell line (A-594).
Table 4. Caspse-3, caspase-8, Bax, and Bcl-2 levels for compounds 3f, 3g, 3h, and Staurosporine on human epithelial cancer cell line (A-594).
Compd. Caspase-3Caspase-8BaxBcl-2
Conc (Pg/mL)Fold ChangeConc (ng/mL)Fold ChangeConc (Pg/mL)Fold ChangeConc (ng/mL)Fold Reduction
3f524 ± 58NDNDNDNDNDND
3g587 ± 592.1724315360.856
3h715 ± 6112.3526336370.609
Staurosporine465 ± 471.8521288321.005
Control6510.091915.001
ND: Not Determined.
Table 5. Antioxidant activity of compounds 3f, 3g, and 3h.
Table 5. Antioxidant activity of compounds 3f, 3g, and 3h.
Antioxidant (DPPH Radical Scavenging Activity %)
Comp.100 µM50 µM10 µM
3f88.576.861.3
3g92.480.270.7
3h96.583.973.5
Trolox95.282.577.6
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El-Sheref, E.M.; Bräse, S.; Tawfeek, H.N.; Alasmary, F.A.; Youssif, B.G.M. Synthesis, Antioxidant and Antiproliferative Actions of 4-(1,2,3-Triazol-1-yl)quinolin-2(1H)-ones as Multi-Target Inhibitors. Int. J. Mol. Sci. 2023, 24, 13300. https://doi.org/10.3390/ijms241713300

AMA Style

El-Sheref EM, Bräse S, Tawfeek HN, Alasmary FA, Youssif BGM. Synthesis, Antioxidant and Antiproliferative Actions of 4-(1,2,3-Triazol-1-yl)quinolin-2(1H)-ones as Multi-Target Inhibitors. International Journal of Molecular Sciences. 2023; 24(17):13300. https://doi.org/10.3390/ijms241713300

Chicago/Turabian Style

El-Sheref, Essmat M., Stefan Bräse, Hendawy N. Tawfeek, Fatmah Ali Alasmary, and Bahaa G. M. Youssif. 2023. "Synthesis, Antioxidant and Antiproliferative Actions of 4-(1,2,3-Triazol-1-yl)quinolin-2(1H)-ones as Multi-Target Inhibitors" International Journal of Molecular Sciences 24, no. 17: 13300. https://doi.org/10.3390/ijms241713300

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