Design, synthesis, anticancer and molecular docking study of furo[2,3-c]quinolone derivatives†

Mininath K. Bhalmode^a, Pradip R. Thorve^b, Mubarak H. Shaikh^c, Rizwan Ali^d, Sarah Huwaizi^d, Sneha Rochlani^e, Prafulla Choudhari^e, Yasinalli Tamboli*^d and Bapurao B. Shingate*^a
aDepartment of Chemistry, Dr Babasaheb Ambedkar Marathwada University, Chhatrapati Sambhaji Nagar 431004, India. E-mail: bapushingate@gmail.com
^bLate Ramchandra Dada Dhas Senior College, Deulgaon Ghat, Ashti, Beed 414202, Maharashtra, India
^cDepartment of Chemistry, Radhabai Kale Mahila Mahavidyalaya, Ahmednagar 414001, Maharashtra, India
^dKing Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs, Riyadh 14811, Saudi Arabia. E-mail: yasinmedchem@gmail.com
^eDepartment of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur 416013, Maharashtra, India

First published on 24th July 2025

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1. Introduction

Cancer, the uncontrolled growth of abnormal cells, remains a significant global health issue and is a leading cause of death worldwide.¹ According to a 2018 report,² cancer was responsible for nearly 9.6 million deaths, highlighting its severe impact. The World Health Organization (WHO) has noted that cancer accounts for approximately one in every six deaths globally. Despite substantial advancements in chemotherapeutics and anticancer agents in recent decades, these treatments often come with serious side effects, such as organ damage, hair and weight loss, off-target toxicity, and drug resistance.^2–4 This situation underscores the urgent need for new cancer drugs that can effectively inhibit cancer cells while minimizing harm to normal cells. The continuous rise in global spending on cancer medicines, including therapeutic and supportive care, reflects the ongoing challenge of treating this disease effectively. There is a pressing need for the discovery and development of new cancer drugs that offer high efficacy and low side effects, focusing on the specific properties of cancer cells to achieve targeted and potent inhibition. Addressing these challenges should improve the quality of life and outcomes for cancer patients.^5,6

Heterocyclic compounds are crucial in pharmaceuticals owing to their diverse biological activities,^7–11 and among these compounds, quinoline is an important class of heterocycles. Quinoline is an aromatic, nitrogen-containing heterocyclic compound with the chemical formula C₉H₇N. It has a bicyclic structure, consisting of a benzene ring fused to a pyridine ring. The quinoline core is a prominent component of many important drugs, a few of which are shown in Fig. 1.^12–20 These compounds can interact with biological systems in various ways, making them invaluable in drug design and development. Their applications extend beyond medicine to fields such as agriculture, materials science, and bioinformatics, highlighting their broad impact.^21,22

Quinoline moieties are versatile and valuable in medicinal chemistry, and quinoline derivatives have been reported to exhibit anti-inflammatory and analgesic properties,^23–25 making them candidates for treating inflammatory conditions and pain. Certain quinoline compounds have shown antiviral activity against viruses.^26,27 Quinoline and its derivatives may also possess anti-oxidant properties, which can be beneficial in preventing oxidative stress-related diseases. Their diverse biological activities make them crucial in drug design and development in fields such as anticancer,²⁸ antimicrobial,²⁹ anti-inflammatory,³⁰ anti-oxidant,³¹ antitubercular,³² antimalarial,³³ anti-leishmanial,³⁴ antiprotozoal,³⁵ anti-HIV,³⁶ and DNA binding.³⁷

The anti-cancer activity of quinoline derivatives is primarily attributed to their ability to interfere with multiple biological targets and pathways involved in cancer progression Fig. 2.³⁸

Similarly, benzofuran derivatives show promise in inhibiting the growth of different cancer cell lines, including ovarian, breast, lung, pancreatic, colon, cervical, and liver cancers.³⁹ Derivatives such as denthyrsin, HIBE, sulfonamide scaffolds, oxadiazole hybrids, 2-aryl benzofuran-appended 4-amino-quinazoline structural motifs, benzofuran-carboxylic acid hybrids, and thiazolodin-4-one benzofuran derivatives, each demonstrate cytotoxic potential and inhibition of specific targets.^40–48

The furan nucleus is known for its pharmacological activity, and compounds containing furan rings have gained attention due to their promising anticancer properties.^49–53 For example, the furan-2-carboxamide molecule (A)⁵⁴ (Fig. 3) demonstrated strong anti-proliferative activity against a variety of cancer cell lines in vitro. Another compound containing the furan group (B)⁵⁵ showed potent cytotoxic activities at the nanomolar level against different human cancer cell lines, with an IC₅₀ of 2.9 nM in NCI-H460 cells. Additionally, a furan derivative (C)^56,57 significantly reduced cellular microtubule formation in MCF-7 cells, displaying excellent β-tubulin polymerization inhibition activity. Lapatinib is a tyrosine kinase inhibitor used in the treatment of certain types of breast cancer. Specifically, it is effective against cancers that overexpress the HER-2 protein. Lapatinib works by inhibiting the tyrosine kinase activity associated with the HER-2/neu and epidermal growth factor receptor (EGFR), which can help to decrease the growth of cancer cells. The fluorinated phenyl ring is a common feature in many tyrosine kinase inhibitors due to its impact on the drug's binding affinity and selectivity. The introduction of fluorine can enhance the drug's metabolic stability and improve its interaction with the kinase domain (D)^58–60 (Fig. 3).

2. Experimental section

2.1. Instrumentation and materials

All experiments were carried out under aerial conditions in a sealed tube. Solvents were freshly dried using standard procedures before use. Products were purified by flash column chromatography on silica gel (100–200 mesh). Merck pre-coated TLC plates (silica gel ⁶⁰F₂₅₄/0.25 mm) were used for thin-layer chromatography (TLC) analysis. Visualization was accomplished under UV light (254 nm).

¹H NMR spectra were recorded with a Bruker instrument at 298 K in CDCl₃. Signals are assigned as δ values in ppm using residual protonated solvent signals as the internal standard (¹H NMR: CDCl₃: δ 7.26 ppm). Data are reported as: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublet, m = multiplet), and coupling constants in (Hz). ¹³C NMR spectra were recorded with a Bruker spectrometer with complete proton decoupling. Chemical shifts (δ) are reported in ppm with the solvent as the internal reference (¹³C NMR: CDCl₃: δ 77.16 ppm). FT-IR spectra were recorded with a PerkinElmer FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded with a Bruker microTOF-Q II spectrometer. Amines and other chemicals were purchased from Sigma-Aldrich, Alfa-Aesar, Spectrochem, Avra Synthesis, and BLD Pharma and used without further purification.

2.2. General procedure for the synthesis of 4-phenylfuro[2,3-c]quinoline derivatives (3a–z)

In a 25 mL sealed tube, 2-(furan-3-yl)aniline 1 (160 mg, 1.0 mmol, 1 equiv.), phd (42 mg, 0.20 mmol, 20 mol%), FeCl₃ (16 mg, 0.10 mmol, 10 mol%), and TsOH·H₂O (17 mg, 0.10 mmol, 10 mol%) were added in nitrobenzene (5.0 mL) and then amine 2 (1.60 gm, 15.0 mmol, 1.5 equiv.) was added slowly and the reaction mixture was stirred at room temperature under an O₂ balloon (1 atm) for approximately 5 minutes. The tube was then capped and placed in a preheated oil bath at 80 °C for 36 h. Upon completion, the reaction was quenched with water (3 × 10 mL), and the mixture was extracted with ethyl acetate or DCM (3 × 10 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (100–200 or 200–400 mesh) with hexane/ethyl acetate as eluent to obtain the target compound 3a–z.

2.3. The synthesis of 4-(furo[2,3-c]quinolin-4-yl)phenyl-4-([1,1′-biphenyl]-4-yl)-4-oxobutanoate (3z)

In a 25 mL sealed tube, 4-(furo[2,3-c]quinolin-4-yl)phenol 3z′ (261 mg, 1.0 mmol, 1.0 equiv.), and 4-([1,1′-biphenyl]-4-yl)-4-oxobutanoic acid (381 mg, 1.0 mmol, 1.5 equiv.) were added in CH₂Cl₂ (5.0 mL) at 0–5 °C. Then DCC (515 mg, 1.0 mmol, 2.5 equiv.) and DMAP (61 mg, 1.0 mmol, 0.5 equiv.) were added sequentially to the cold reaction mixture. After 30–40 min, the ice-water cooling bath was removed and the resulting suspension was stirred vigorously at room temperature for 16 h. The reaction mixture was then concentrated in a vacuum and the residue was purified by flash column chromatography over silica gel (100–200 or 200–400 mesh) with hexane/ethyl acetate (15:85) as eluent to obtain compound 3z as a colourless solid; R_f = 0.60; yield = 65%. FT-IR (ν_max cm⁻¹): 1132, 1201, 1356, 1432, 1577, 1757 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ ppm 8.57 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.2 Hz, 3H), 7.95 (d, J = 2.6 Hz, 1H), 7.72 (d, J = 8.2 Hz, 3H), 7.63 (t, J = 7.2 Hz, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.42 (d, J = 7.4 Hz, 1H), 7.38–7.34 (m, 3H), 3.51 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.5 Hz, 2H). ¹³C NMR (125 MHz, CDCl₃): δ ppm 197.6, 171.5, 152.2, 147.5, 147.1, 146.2, 144.4, 143.8, 140.0, 135.3, 134.1, 131.0, 130.4, 130.3, 129.1, 128.8, 128.4, 127.9, 127.5, 127.4, 126.6, 123.4, 123.3, 121.9, 105.7, 33.7, 28.8. HRMS (ESI⁺) m/z: calcd for C₃₃H₂₄NO₄ [M + H]⁺: 498.1700; found: 498.1710.

3. Results and discussion

3.1. Chemistry

Quinoline and furan derivatives form a considerable class of biologically active scaffolds. Merging two or more pharmacophores can introduce new molecular templates that may exhibit considerable biological properties. We have synthesized a series of furo[2,3-c]quinolone derivatives (3a–z′) using 2-(furan-3-yl)aniline derivative (1) and substituted benzylamine (2) in nitrobenzene with 1,10-phenanthroline-5,6-dione (phd)/FeCl₃ as a catalyst. p-Toluene sulfonic acid (TsOH·H₂O) was utilized as an additive under aerial conditions at 80 °C to afford moderate to good yields (Scheme 1).⁶¹ Further, compound 3z′ coupled with 4-([1,1′-biphenyl]-4-yl)-4-oxobutanoic acid in the presence of DCC and DMAP in dichloromethane at 0–5 °C to furnish 4-(furo[2,3-c]quinolin-4-yl)phenyl 4-([1,1′-biphenyl]-4-yl)-4-oxobutanoate (3z) in excellent yield (Scheme 2). The synthesized furo[2,3-c]quinolone derivatives 3a–z are shown in Scheme 1.

We have proposed a plausible mechanism in Scheme 3. First, benzylamine 2 reacts with Fe(phd)₂Cl₃ catalyst to generate the imine intermediate 2′. The generated imine intermediate 2′ then undergoes transamination with 1 in the presence of an additive (TsOH·H₂O) through intramolecular cyclization and aerial oxidation to generate the desired product 3. On the other hand, the catalyst intermediate III undergoes oxidation in the presence of oxygen to generate the intermediate IV, which is re-oxidized in the presence of 2 to close the catalytic cycle.

Furo-quinoline derivatives (3a–z) were characterized based on their analytical data and spectroscopic methods such as FT IR, ¹H NMR, ¹³C NMR, and HRMS. The 1542 cm⁻¹ peak in the FT-IR spectrum of compound 3a suggests the presence of an aromatic CN bond, which indicates a nitrogen-containing aromatic system. The 2917 cm⁻¹ peak indicates that C–H bonds are present in the compound. In the ¹H NMR study, the δ 7.91 ppm (doublet) and δ 7.29 ppm (doublet) signals are assigned to the furan ring, which typically shows signals in this region due to the aromatic nature of the furan, and δ 8.51 ppm (doublet), δ 7.11 ppm (doublet) signals correspond to protons on the phenyl ring. The coupling constant (J = 9.0 Hz) suggests that these protons are ortho to each other, and δ 7.69 ppm (triplet) and δ 7.57 ppm (triplet) signals are likely due to protons on the quinoline ring, which is consistent with aromatic protons in this chemical environment.

Compound 3b likely contains a furo-quinoline ring with an aromatic CN and a p-methoxy functional group. In the ¹H NMR spectrum, the δ 3.91 ppm (singlet) signal corresponds to the p-methyl functional group, which is typically observed as a singlet in this region. In the ¹³C NMR spectrum, the signal at δ 55.5 ppm corresponds to the p-methoxy carbon, and δ 146.9 ppm and δ 105.6 ppm signals are associated with carbons attached to the furan ring within the quinoline structure. The δ 114.2 ppm and δ 128.9 ppm signals are suggested to arise from carbons in the phenyl ring, and δ 147.4 ppm and δ 146.9 ppm signals likely correspond to carbons in the quinoline ring. The proximity of these shifts suggests that they are associated with carbons adjacent to the electronegative atoms within the quinoline structure. In the HRMS analysis, the calculated [M + H]⁺ m/z for compound 3b is 276.1019 and the observed peak is at m/z 276.1020, which confirms that compound 3b was formed. The calculated and observed mass in the HRMS further supports the identity of the compound. These overall spectral data suggested that compound 3b was formed.

Similarly, for compound 3z, the FT-IR absorbance at 1132 cm⁻¹ indicates C–O stretching vibrations, likely from a furan ring (1201 cm⁻¹). The C–C stretching frequency in a benzene ring at 1432 cm⁻¹ could also be associated with aromatic C–C bond stretching. The 1577 cm⁻¹ band is consistent with the CN stretching frequency for the quinoline ring. The 1757 cm⁻¹ band suggests the stretching frequency of the carbonyl ester functional group. Based on the ¹H NMR spectrum, aliphatic protons at δ 3.51 ppm (t, J = 6.5 Hz, 2H) suggest the presence of two protons in an aliphatic environment close to a carbonyl group, likely on a methylene (–CH₂–) group adjacent to a carbonyl carbon. Similarly, the triplet at δ 3.10 ppm (t, J = 6.5 Hz, 2H) indicates another set of two aliphatic protons on a methylene group adjacent to an ester carbonyl group. In the aromatic protons, doublets at δ 7.95 ppm (d, doublet) and δ 8.28 ppm (d, doublet) are consistent with protons on a furan ring. The multiplicity and coupling constants are consistent with aromatic protons that are part of an extended conjugated system, possibly indicating the presence of a substituted benzene ring. The data suggest a molecule with multiple aromatic rings, including a furan ring, a quinoline ring, and a phenyl ring.

In the ¹³C NMR spectrum, the signal at δ 197.6 ppm indicated a ketone carbonyl carbon (CO). The ketone typically resonates downfield due to the de-shielding effect of the electronegative oxygen atom. The δ 171.5 ppm peak indicates the presence of an ester carbonyl carbon (CO). The ester carbonyl carbons are slightly shielded compared to ketones due to the electron-donating effect of the adjacent oxygen atom. The δ 33.7 ppm signal corresponds to the aliphatic carbon that is near a carbonyl group. Similarly, the δ 28.8 ppm peak is also indicative of an aliphatic carbon. These chemical shifts suggest that the molecule contains multiple functional groups, including a ketone, an ester, a quinoline ring, and a furan ring. The presence of quinoline and furan rings, along with the specific positioning of the carbonyl groups and aliphatic carbon atoms, is also indicated. In the HRMS study, the calculated mass for [M + H]⁺ is 498.1700 and the observed mass for [M + H]⁺ is 498.1710. The difference between the calculated and observed mass is extremely small, which suggests that the molecular formula and structure corresponding to the calculated mass are likely correct. This mass spectrometry further supports the identification of compound 3z. The FT IR, ¹H NMR, ¹³C NMR and HRMS data thus confirm that compound 3z was formed.

3.2. Anti-cancer activity

The initial screening for cell viability of the KAMRC2 cancer cell line with synthesized compounds 3a–z was performed using the MTT assay. Cells were exposed to a concentration range of 100 to 0 μM, with mitoxantrone used as a positive control for cytotoxicity. Among the tested compounds, 4-(2-bromophenyl)furo[2,3-c]quinolone displayed notable cytotoxic effects, moderately inhibiting tumor cell growth, as shown in Fig. 4. Halo-aryl derivatives exhibit excellent activity compared to all non-halogenated derivatives. Notably, 2-bromophenyl derivative 3h was found to be active while 4-bromophenyl derivative 3i was inactive. Compound 3h (IC₅₀ 2.79 μM) is frontrunner among the series as compared to the standard anticancer agent, mitoxantrone (IC₅₀ 0.1 μM).

The IC₅₀ values shown in Fig. 5 and Table 1 indicate differential cytotoxic effects of compound 3h compared to the standard drug, mitoxantrone, across the three cell lines (KAIMRC2, MDAMB231, HCT8). The IC₅₀ values represent the concentration at which 50% inhibition of cell viability is observed, a critical marker of cytotoxic potency. Compound 3h, with an IC₅₀ value of 2.79 μM, suggests excellent cytotoxicity against KAIMRC2 cell lines. It shows potential as an anti-breast-cancer agent. The IC₅₀ value of 64.37 μM is notably high against another breast cancer cell line MDAMB231, suggesting that compound 3h is less effective in inhibiting cell viability in this cell line, especially when compared to mitoxantrone (IC₅₀ 0.34 μM). Finally, compound 3h, with an IC₅₀ of 15.95 μM for the HCT8 cell line, exhibits some cytotoxic activity but remains far less potent than mitoxantrone (IC₅₀ 0.18 μM). These findings underscore the potential but limited effectiveness of compound 3h as an anticancer agent when compared to mitoxantrone. It was observed that compound 3h exhibits five-fold killing ability against breast cancer cells KAIMRC2 compared to colon cancer cells, HCT8.

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3.3. Apoptosis assay by high-content imaging (HCI)

To investigate cell death behaviour, KAIMRC2 and HCT8 were treated with compound 3h for 48 hours; the HCI results are shown in Fig. 6. The cells were exposed to two concentrations (a high dose of 50 μM and a near-IC₅₀ dose of 12.5 μM), with DMSO as the negative control. Compound 3h demonstrated a dose-dependent cytotoxic effect in both cell lines, with greater activity observed in the breast cancer cell line (KAIMRC2) compared to the colon cancer cell line (HCT8), confirming our previous MTT assay results.

3.4. Cell morphology by TEM

TEM images of KAIMRC2 cells that were untreated or treated with compound 3h are shown in Fig. 7. As expected, untreated cells remained healthy and normal with all cellular components intact. Conversely, after treatment with the active compound 3h, significant morphological changes were observed in the KAIMRC2 cells. The cells displayed distinct signs of apoptosis, including cell shrinkage, nuclear condensation and nuclear membrane rupture.

3.5. The wound healing assay

The wound healing assay was performed on breast cancer cell line (KAIMRC2) and the human colon cancer cell line (HCT8) by treatment with compound 3h for 48 h. Fig. 8 clearly shows a scratch area at 0 h in both. Notably, complete wound closure was observed in the case of both KAIMRC2 and HCT8, indicating a high level of cell migration and proliferation. The wound size of the HCT8 cell line was twice that of the KAIMRC2 cell line, which is why a small area remained uncovered after 48 h in the HCT8 cell line. The rate of wound closure was similar for both the cell lines, which indicates that although 3h has a cytotoxic effect on the cells, it does not affect cell migration or the proliferation potential of the cell lines.

3.6. Western blot analysis

Western blot analysis was performed to evaluate the expression levels of β-actin, mTOR (mammalian target of rapamycin), Bcl-2 (anti-apoptotic marker), and Bax (pro-apoptotic marker) in the cancer cells. Fig. 9 displayed the result of expression on KAIMRC2 cell lines after treatment with compound 3h compared with a standard anticancer drug (mitoxantrone). Compound 3h failed to downregulate any of the three Bax, Bcl-2, and mTOR expressions. Hence, compound 3h induces cell death by an unknown mechanism through different pathways and may serve as a promising anticancer agent.

3.7. Computational study

4. Conclusion

We have synthesized a series of furo[2,3-c]quinolone derivatives (3a–z′) by using the amine oxidase-inspired catalyst 1,10-phenanthroline-5,6-dione/FeCl₃ via aerobic amine dehydrogenation in moderate to good yields. Compound 3h exhibited excellent anti-cancer activity, especially against the breast cancer cell line KAIMRC2. High-content imaging (HCI) analysis demonstrated that treatment with compound 3h induced a dose-dependent cytotoxic effect, highlighting its potent cell death-inducing activity. Transmission electron microscopy (TEM) images of the KAIMRC2 cell line revealed distinct morphological differences between untreated cells and cells treated with compound 3h. As expected, the untreated cells appeared healthy and normal, with all cellular components intact, while the treated cells exhibited significant structural alterations, highlighting the cytotoxic impact of compound 3h. Furthermore, the wound healing assay revealed that compound 3h has no effect on the migratory or proliferative behaviours of the breast cancer cell line KAIMRC2 and the human colon cancer cell line HCT8. Western blot analysis revealed that cell death induced by the compound occurs through an alternative pathway or mechanism, independent of the mTOR and Bcl-2/Bax regulatory axis. Molecular docking studies revealed a significant correlation between the compounds’ binding scores and their biological activities, supporting the experimental findings and highlighting the potential of these derivatives as effective therapeutic agents. Therefore, both in vitro and in silico findings indicate that furo[2,3-c]quinolone derivatives represent a promising scaffold for further structural optimization toward the development of effective anticancer agents.

Author contributions

MKB, PRT and MHS performed the experimental and characterization work and prepared the manuscript. RA, SH and YT carried out the biological activity studies. SR and PC carried out the computational study. BBS and YT designed and monitored the project and reviewed the manuscript.

Conflicts of interest

The authors declare that they have no conflict of interest.

Data availability

All data have been included in the ESI.†

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5nj01012h

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