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. 2024 Nov 25;15(12):2150–2157. doi: 10.1021/acsmedchemlett.4c00438

Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity

Akram H Abd El-Haleem †, Manar Abd El-karim Kassem †, Mohamed R Elnagar ‡,§, Safinaz E-S Abbas ∥, Ahmed M El Kerdawy ∥,⊥, Ahmed K B A W Farouk ∥,*
PMCID: PMC11647721  PMID: 39691520

Abstract

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New derivatives 4a–d, 6, 7a–d, 8a–c, 9, 11a, 11b, 12a–f, 13a–c, and 14 were synthesized and evaluated for their VEGFR-2 inhibition. Compounds 4c, 7b, and 7c showed remarkable enzyme inhibition (IC50 = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC50 = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound 7b displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC50 = 6.66 and 8.51 μM) compared to sorafenib (IC50 = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of 7b in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound 7b revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of 7b showed inhibition of wound closure. Additionally, molecular modeling studies of compounds 4c, 7b, and 7c were carried out.

Keywords: Furan, Furopyrimidine, VEGFR-2, Cytotoxicity, Sorafenib, A549, HT-29

Cancer arises from defects in inherited genetic material.1 These defects can lead to activation of the oncogenes, which promote cancer formation and inhibit tumor suppressor genes.2

Blood supply and blood vessel formation are essential for solid tumor growth as well as metastasis.3 Interestingly, angiogenesis is regulated by proangiogenic and antiangiogenic factors.4 Vascular endothelial growth factor (VEGF), a proangiogenic factor, interacts with the kinase domain of the vascular endothelial growth factor receptor (VEGFR) to initiate the development of new blood or lymphatic vessels during the early stages of angiogenesis.5−7 Therefore, inhibiting VEGFR kinase is a potential strategy for developing antiangiogenic agents.8,9

The binding patterns of many VEGFR-2 inhibitors reveal that the binding pocket includes (1) the hinge region, (2) the gate area, and (3) the allosteric hydrophobic back pocket. Sunitinib (I) competes with ATP at the hinge region,10 while sorafenib (II) fits into the hinge region and extends through the gate area into the allosteric pocket11 (Figure 1).

Figure 1.

Figure 1

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Binding modes of some FDA-approved VEGFR-2 inhibitors.12

Several furo[2,3-d]pyrimidine derivatives were discovered as promising VEGFR-2 inhibitors13−15 (Figure 2). Compound III showed promising VEGFR-2 inhibition (IC50 = 122 nM) compared to sorafenib (IC50 = 90.0 nM).13 Furthermore, IV and V elicited good to equipotent VEGFR-2 inhibition (IC50 = 58.0 and 41.4 nM, respectively) in comparison to sorafenib (IC50 = 41.2 nM).14 Moreover, they demonstrated potent to moderate cytotoxicity against HUVECs (IC50 = 22.6 and 61.2 μM, respectively) relative to sorafenib (IC50 = 20.6 μM).14 Compound VI displayed superior VEGFR-2 inhibition (IC50 = 9.30 nM) compared to sunitinib (IC50 = 18.9 nM).15

Figure 2.

Figure 2

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Examples of reported furopyrimidine derivatives as VEGFR-2 inhibitors.

Based on the previous studies, the current research describes different approaches to synthesize and biologically evaluate novel furan- and furopyrimidine-based derivatives 4a–d, 6, 7a–d, 8a–c, 9, 11a, 11b, 12a–f, 13a–c, and 14 as VEGFR-2 inhibitors. Our scaffolds are designed to bind to the hinge region, and the extended side chains are proposed to interact with the gate area.

Accordingly, the most active compounds as VEGFR-2 inhibitors were screened for in vitro cytotoxicity. Moreover, the most cytotoxic compound was subjected to cell cycle analysis, apoptosis, Bax/Bcl2, wound healing, and Western blot assays. Finally, a molecular modeling study was applied to the most active derivatives.

The synthetic pathways used for the preparation of the target compounds are illustrated in Schemes 1–3. In Scheme 1, benzoin (1),16 2-aminofuran-3-carbonitrile 2(17,18) and pyrimidin-4-amine 3(19,20) were synthesized according to the reported procedures.

Scheme 1.

Scheme 1

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Reagents and conditions: (i) KCN, aqueous ethanolic solution, reflux, 1.5 h. (ii) Malononitrile, triethylamine, DMF, r.t., 24 h. (iii) Formamide, reflux, 2 h. (iv) 4a and 4b, pyridine, reflux, 12 h; 4c and 4d, dry benzene, anhydrous K2CO3, reflux, 15 h.

Scheme 3.

Scheme 3

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Reagents and conditions: (i) Triethyl orthoformate, acetic anhydride, reflux, 7 h. (ii) Hydrazine hydrate, absolute ethanol, r.t., 1 h. (iii) Appropriate isatin derivatives, absolute ethanol, reflux, 2 h. (iv) Appropriate isothiocyanate derivatives, absolute ethanol, reflux, 10–12 h. (v) Appropriate acid chloride derivatives, pyridine, reflux, 10–12 h. (vi) Ethyl cyanoacetate, absolute ethanol, reflux, 6 h.

Acylation of 3 with the appropriate benzoyl chlorides yielded the monosubstituted benzamide derivatives 4a, 4c, and 4d as well as the disubstituted congener 4b. Acylation in pyridine under reflux afforded only 4a and 4b, whereas 4c and 4d were not produced even after modification of the reaction conditions. In contrast, 4c and 4d were obtained by refluxing 3 with 4-nitro- or 4-methylbenzoyl chloride in benzene in the presence of anhydrous potassium carbonate.

Furthermore, formimidate 5 was synthesized by heating 2 under reflux with triethyl orthoformate in the presence of acetic anhydride as reported.21 4-Iminofuropyrimidin-3-amine 6 was prepared by heating formimidate 5 under reflux with phenylhydrazine in ethanol (Scheme 2). Attempts to obtain furo[2,3-d]pyrimidines via the reaction of formimidate 5 with the appropriate aliphatic or aromatic amines (tert-butylamine, 4-chloroaniline, 4-bromoaniline, or 4-anisidine) in ethanol under reflux did not afford the desired furo[2,3-d]pyrimidines, even after changing the reaction conditions. Surprisingly, 3-cyanoformimidamides 7a–d were obtained (Scheme 2). Interestingly, signal duplication was observed for 7a–d in 1H and 13C NMR spectra, revealing the presence of these compounds in cis (Z) and trans (E) forms22−24 (Figure 3).

Scheme 2.

Scheme 2

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Reagents and conditions: (i) Triethyl orthoformate, acetic anhydride, reflux, 7 h. (ii) Phenylhydrazine, absolute ethanol, reflux, 3 h. (iii) Appropriate aliphatic or aromatic amine derivatives, absolute ethanol, reflux, 10–12 h. (iv) Semicarbazide HCl, absolute ethanol, TEA, reflux, 10 h.

Figure 3.

Figure 3

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Z and E geometrical isomeric forms of compounds 7a–d.

Regardless of the reaction time or the type of amine, heating formimidate 5 with isopropylamine, cyclohexylamine, or 2-ethylaniline in ethanol under reflux furnished the furo[2,3-d]pyrimidine derivatives 8a–c (Scheme 2). Compound 9 was produced by heating formimidate 5 under reflux with semicarbazide hydrochloride in ethanol in the presence of triethylamine (Scheme 2).

The reaction of hydrazine hydrate and formimidate 5, based on the reported procedure,25,26 afforded 4-iminofuropyrimidinamine 10. Compounds 11a and 11b were obtained by heating 10 under reflux with the appropriate isatin derivatives in absolute ethanol (Scheme 3). Reaction of 10 with the appropriate isothiocyanates in absolute ethanol under reflux afforded furotriazolopyrimidines 12a–f (Scheme 3). Refluxing 10 with the appropriate benzoyl chlorides in pyridine produced furotriazolopyrimidines 13a–c. Furotriazolopyrimidine acetonitrile derivative 14 was obtained by heating 10 under reflux with ethyl cyanoacetate in absolute ethanol.

The entire set of compounds were exposed to a VEGFR-2 kinase assay to assess their inhibitory activity using sorafenib as a reference standard. Results are presented as IC50 (nM) ± standard deviation (SD) in Table 1. The synthesized compounds showed VEGFR-2 inhibitory activity (IC50 = 42.45–196 nM) compared to sorafenib (IC50 = 41.1 nM).

Table 1. IC50 Values* of the Tested Compounds on the Inhibitory Activity against the VEGFR-2 Kinase Assay.

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graphic file with name ml4c00438_0009.jpg

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a

Significant difference at p < 0.05.

b

Nonsignificant difference at p < 0.05.

*

IC50 values are the mean ± SD of three separate experiments.

Regarding furans 7a–d, it was noticed that they display a broad range of inhibition (IC50 = 42.5–189 nM). Compounds 7a and 7d showed the least inhibitory activity (IC50 = 129 and 189 nM, respectively), whereas 7b and 7c displayed the most potent inhibition (IC50 = 42.5 and 52.5 nM, respectively).

Furo[2,3-d]pyrimidines, including 4a–d, 6, 8a–c, and 9, exhibited varied VEGFR-2 inhibition (IC50 = 57.1–196 nM) compared to sorafenib (IC50 = 41.1 nM). Among these derivatives, 4c displayed the most potent inhibitory activity (IC50 = 57.1 nM). However, benzamides 4a, 4b, and 4d did not show any significant inhibition (IC50 = 90.0, 99.8, and 196 nM, respectively). Furopyrimidines 6, 8a–c, and 9 demonstrated moderate to weak enzyme inhibition (IC50 = 67.8–170 nM). Compounds 6 and 9 showed moderate activity (IC50 = 85.2 and 67.8 nM, respectively), while 8a, 8b, and 8c did not display remarkable inhibition (IC50 = 99.0, 129, and 170 nM, respectively).

Meanwhile, furopyrimidotriazinoindoles 11a and 11b disclosed weak to moderate enzyme inhibition (IC50 = 144 and 85.1 nM, respectively), with 11b being more potent than 11a.

It was observed that furotriazolopyrimidines 12a–f, 13a–c, and 14 show moderate to weak enzyme inhibition (IC50 = 76.6–152 nM), where 13c and 14 elicited acceptable enzyme inhibition (IC50 = 83.6 and 76.6 nM, respectively). The other derivatives showed weak VEGFR-2 inhibition (IC50 = 96.2–152 nM).

Finally, we can conclude that 7b and 7c in addition to 4c display the most potent enzyme inhibition (IC50 = 42.5, 52.5, and 57.1 nM, respectively) compared to sorafenib (IC50 = 41.1 nM). Compounds bearing electron-withdrawing groups were more potent than those having electron-donating ones.The best enzyme inhibition was noticed in furans 7b and 7c. Among furopyrimidines 4a–d, 6, 8a–c, and 9, compound 4c exhibited significant inhibition (IC50 = 57.1 nM), while furopyrimidotriazinoindoles 11a and 11b disclosed moderate to weak inhibition (IC50 = 144 and 85.1 nM, respectively). Also, acetonitrile 14 displayed moderate inhibition (IC50 = 76.6 nM) among the other furotriazolopyrimidines 12a–f and 13a–c (IC50 = 83.6 to 152 nM).

The most potent derivatives in the in vitro VEGFR-2 kinase assay, 4c, 7b, and 7c, were screened for their antiproliferative activity against HepG2,27 MCF-7,28 A549,29 PC3,30 and HT-2931 cancer cell lines, where VEGFR-2 is highly expressed, in addition to the normal lung fibroblast cell line WI-38 using sorafenib as a positive control (see p S69 in the Supporting Information).

Concerning HepG2, the examined derivatives elicited an IC50 range of 7.28–13.1 μM. 7b exhibited a significant cytotoxic effect (IC50 = 7.28 μM) compared to sorafenib (IC50 = 5.09 μM), while 4c and 7c displayed a moderate cytotoxic effect (IC50 = 13.1 and 11.2 μM, respectively).

With regard to MCF-7, the tested congeners showed an IC50 range of 6.72–11.4 μM. Compound 7b showed significant cytotoxic activity (IC50 = 6.72 μM) comparable to that of sorafenib (IC50 = 5.17 μM), whereas 4c and 7c showed a moderate cytotoxic effect (IC50 = 11.4 and 9.06 μM, respectively).

In view of A549, the tested compounds displayed IC50 values ranging from 6.66 to 14.5 μM. Compound 7b showed an equipotent antiproliferative activity (IC50 = 6.66 μM) relative to sorafenib (IC50 = 6.60 μM), whereas 4c and 7c exhibited a moderate cytotoxic effect (IC50 = 14.5 and 10.1 μM, respectively).

With regard to HT-29, the tested compounds revealed an IC50 range of 8.51–21.4 μM. Also, 7b demonstrated superior cytotoxic activity (IC50 = 8.51 μM) comparable to that of sorafenib (IC50 = 8.78 μM), whereas 4c and 7c showed moderate inhibitory activity (IC50 = 21.4 and 12.1 μM, respectively).

It was noticed that the examined derivatives give a mild to low activity on PC3 with an IC50 range of 14.5–22.1 μM. 7b displayed moderate activity (IC50 = 14.5 μM) in comparison to sorafenib (IC50 = 11.0 μM), whereas 4c and 7c revealed low cytotoxicity (IC50 = 22.1 and 23.2 μM, respectively).

It is worth mentioning that 7b displays the most potent anticancer activity against the chosen cell lines with selective cytotoxicity against A549 and HT-29 (IC50 = 6.66 and 8.51 μM, respectively). Also, 7c showed significant anticancer activity against HepG2, MCF-7, A549, and HT-29 more than 4c.

Additionally, 4c, 7b, and 7c showed a good safety profile against the normal WI-38 cell line. The selectivity index (SI) was calculated especially for A549 and HT-29 cell lines, and 7b elicited the most potent cytotoxicity (see p S69 in the Supporting Information).

The most potent compound 7b was evaluated for its effect on cell progression and apoptotic induction in HT-29. The results demonstrated that compound 7b causes cell growth arrest at G2/M based on accumulation of DNA content in HT-29 cells in addition to elevation of total apoptosis percentage (see p S87 in the Supporting Information).

The impact of 7b on Bax and Bcl-2 was assessed to provide confirmed evidence for apoptosis induction (see p S87 in the Supporting Information).

Western blot of 7b was performed in HT-29 at three variable values (IC50, 0.5·IC50, and 0.1·IC50) relative to control untreated cells for 24 h. The results revealed that 7b greatly reduces VEGFR-2 expression in a dose-dependent manner. (see p S90 in the Supporting Information).

An in vitro wound healing assay was used to determine the antimetastatic activity of compound 7b on HT-29 at 0.1·IC50 and 0.5·IC50 values against untreated control cells compared with sorafenib. Healing was demonstrated after 48 h, and the wound closure % was measured. Compound 7b exerted a noticeable inhibition in wound closure (see p S91 in the Supporting Information).

A molecular docking study was performed to investigate the binding patterns of 4c, 7b, and 7c in the binding site of VEGFR-2 and to rationalize their inhibitory activity. In the present study, the X-ray crystallographic structure of VEGFR-2 (PDB ID 4ASD)32,33 was utilized to perform the molecular docking simulations. Initially, cognate docking was carried out to validate the docking protocol by docking the cocrystallized kinase inhibitor (sorafenib) in the VEGFR-2 kinase domain. The cognate docking validation step precisely restored the interaction pattern of the cocrystallized inhibitor, demonstrating that the implemented docking setup is appropriate for the intended docking study. This is shown by the low RMSD value (0.326 Å) and by the ability of the obtained pose to restore the key interactions attained by the cocrystallized inhibitor with the important residues at the kinase domain (Glu885, Cys919, and Asp1046; for more details, see the Supporting Information).

Compounds 4c, 7b, and 7c show a similar binding pattern in the hinge region of VEGFR-2 kinase domain (see p S94 in the Supporting Information). The binding mode of the investigated compounds involves their accommodation in the kinase domain front pocket (hinge region). In 4c, N1 of the pyrimidine ring and the NO2 group form conventional non-covalent H-bonds with Cys919 and Asp1046, respectively (Figures 4). N1 of the formimidamide moiety in 7b and 7c catches the hinge region through H-bonding with Cys919, and additionally, in the gate area, the 4-Cl of 7b and 4-Br of 7c interact with Glu885 and Asp1046, respectively, which are essential residues at the kinase domain, and this may contribute to their remarkable enzyme inhibition. Furthermore, the interactions between furopyrimidine and formimidamide in the binding site of the enzyme are presented in the Supporting Information.

Figure 4.

Figure 4

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(a) 2D diagram and (b) 3D diagram showing interactions of compound 4c docking pose with the key residues in the VEGFR-2 active site (distances in Å).

Molecular dynamics simulations were performed for 100 ns for 4c and 7b in the VEGFR-2 kinase domain and compared to the unliganded VEGFR-2 kinase domain starting from the obtained molecular docking structures of the 4c/VEGFR-2 and 7b/VEGFR-2 complexes.34,35 MD trajectories were analyzed and used for calculating RMSD, RMSF, and Rg for the different simulations, which show system stability and simulation quality (see p S98 in the Supporting Information).

The 4c/VEGFR-2 and 7b/VEGFR-2 complexes displayed considerable stability, showing average RMSD values of 0.202 ± 0.041 and 0.191 ± 0.017 nm, respectively, with the unliganded VEGFR-2 kinase domain showing an average RMSD value of 0.201 ± 0.041 nm. The lower average RMSD value of the 7b/VEGFR-2 complex compared with those of the unliganded kinase domain and 4c/VEGFR-2 complex indicated that it stabilizes the VEGFR-2 kinase domain, which can rationalize its potent inhibitory activity and its higher potency over 4c. For more details, see p S98 in the Supporting Information.

In summary, 25 derivatives were synthesized and screened for their VEGFR-2 inhibitory activity. 4c, 7b, and 7c elicited significant enzyme inhibition (IC50 = 57.1, 42.5, and 52.5 nM, respectively). Moreover, 4c, 7b, and 7c were assessed for their cytotoxicity against HepG2, MCF-7, A549, PC3, and HT-29 cells in addition to WI-38 cells. Compound 7b displayed the most potent cytotoxicity against the chosen cell lines with selective cytotoxicity against A549 and HT-29 (IC50 = 6.66 and 8.51 μM, respectively). Also, it caused cell cycle arrest at the G2/M phase in HT-29, and the apoptotic assay of 7b revealed an elevation of total apoptosis percentage. In addition, 7b caused an elevation of Bax along with a decrease in Bcl-2, which confirm its apoptosis induction. Western blot analysis of 7b showed greatly reduced VEGFR-2 expression in HT-29 at 0.1·IC50, 0.5·IC50, and IC50, indicating that the inhibition occurs in a dose-dependent manner. Furthermore, 7b exerted noticeable inhibition in wound closure compared to sorafenib and the control cell. The molecular modeling study of 4c, 7b, and 7c indicated that their interaction pattern is consistent with their VEGFR-2 inhibition.

Glossary

Abbreviations

VEGFR-2

vascular endothelial growth factor receptor

HepG2

human liver cancer cell line

MCF-7

breast cancer cell line

A549

lung cancer cell line

HT-29

colon cancer cell line

PC3

prostate cancer cell line

WI-38

the normal fibroblast cell line

VEGF

vascular endothelial growth factor

ATP

adenosine triphosphate

HUVECs

human umbilical vein endothelial cells

SI

selectivity index

TEA

triethylamine

K2CO3

potassium carbonate

DMF

dimethylformamide

PDB

Protein Data Bank

RMSD

root-mean-square deviation

RMSF

root-mean-square fluctuation

Rg

radius of gyration

NMR

nuclear magnetic resonance

DMSO

dimethyl sulfoxide

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00438.

  • Additional experimental procedures, biological assays, and in silico studies (PDF)

These studies were not funded by any organization or entity with a financial interest.

The authors declare no competing financial interest.

Supplementary Material

ml4c00438_si_001.pdf (7.2MB, pdf)

References

  1. Dhiwar P. S.; Purawarga Matada G. S.; Pal R.; Singh E.; Ghara A.; Maji L.; Sengupta S.; Andhale G. An assessment of EGFR and HER2 inhibitors with structure activity relationship of fused pyrimidine derivatives for breast cancer: a brief review. J. Biomol. Struct. Dyn. 2024, 42 (3), 1564–1581. 10.1080/07391102.2023.2204351. [DOI] [PubMed] [Google Scholar]
  2. Shiao H.-Y.; Coumar M. S.; Chang C.-W.; Ke Y.-Y.; Chi Y.-H.; Chu C.-Y.; Sun H.-Y.; Chen C.-H.; Lin W.-H.; Fung K.-S.; et al. Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor. J. Med. Chem. 2013, 56 (13), 5247–5260. 10.1021/jm4006059. [DOI] [PubMed] [Google Scholar]
  3. El-Kenawi A. E.; El-Remessy A. B. Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales. Br. J. Pharmacol. 2013, 170 (4), 712–729. 10.1111/bph.12344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Huang Z.; Bao S.-D. Roles of main pro-and anti-angiogenic factors in tumor angiogenesis. World J. Gastroenterol. 2004, 10 (4), 463. 10.3748/wjg.v10.i4.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ghalehbandi S.; Yuzugulen J.; Pranjol M. Z. I.; Pourgholami M. H. The role of VEGF in cancer-induced angiogenesis and research progress of drugs targeting VEGF. Eur. J. Pharmacol. 2023, 949, 175586 10.1016/j.ejphar.2023.175586. [DOI] [PubMed] [Google Scholar]
  6. Metwally W. M.; Hegazy G.; Eid S.; Serya R. A. T.; Abou El Ella D. A. Design and Synthesis of quinazoline derivatives: Biological evaluation for their Anticancer and VEGFR inhibitory activities. Life Sci. J. 2016, 13 (2), 57–68. 10.7537/marslsj130216.10. [DOI] [Google Scholar]
  7. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti-and pro-angiogenic therapies. Genes Cancer 2011, 2 (12), 1097–1105. 10.1177/1947601911423031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Abdelgawad M. A.; El-Adl K.; El-Hddad S. S.; Elhady M. M.; Saleh N. M.; Khalifa M. M.; Khedr F.; Alswah M.; Nayl A. A.; Ghoneim M. M.; et al. Design, molecular docking, synthesis, anticancer and anti-hyperglycemic assessments of thiazolidine-2,4-diones Bearing Sulfonylthiourea Moieties as Potent VEGFR-2 Inhibitors and PPARγ Agonists. Pharmaceuticals 2022, 15 (2), 226. 10.3390/ph15020226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Tugues S.; Koch S.; Gualandi L.; Li X.; Claesson-Welsh L. Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. Mol. Aspects Med. 2011, 32 (2), 88–111. 10.1016/j.mam.2011.04.004. [DOI] [PubMed] [Google Scholar]
  10. Shehta W.; Agili F.; Farag B.; Youssif S.; Almehmadi S. J.; Elfeky S. M.; El-Kalyoubi S. Synthesis and in vitro study of pyrimidine–phthalimide hybrids as VEGFR2 inhibitors with antiproliferative activity. Future Med. Chem. 2023, 15 (8), 661–677. 10.4155/fmc-2023-0025. [DOI] [PubMed] [Google Scholar]
  11. Blanc J.; Geney R.; Menet C. Type II kinase inhibitors: an opportunity in cancer for rational design. Anti-Cancer Agents Med. Chem. 2013, 13 (5), 731–747. 10.2174/1871520611313050008. [DOI] [PubMed] [Google Scholar]
  12. Eldehna W. M.; El Kerdawy A. M.; Al-Ansary G. H.; Al-Rashood S. T.; Ali M. M.; Mahmoud A. E. Type IIA-Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides. Eur. J. Med. Chem. 2019, 163, 37–53. 10.1016/j.ejmech.2018.11.061. [DOI] [PubMed] [Google Scholar]
  13. Aziz M. A.; Serya R. A.; Lasheen D. S.; Abdel-Aziz A. K.; Esmat A.; Mansour A. M.; Singab A. N. B.; Abouzid K. A. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci. Rep. 2016, 6 (1), 24460. 10.1038/srep24460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Abd El-Mageed M. M.; Eissa A. A.; Farag A. E.-S.; Osman E. E. A. Design and synthesis of novel furan, furo [2,3-d]pyrimidine and furo [3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives as potential VEGFR-2 inhibitors. Bioorg. Chem. 2021, 116, 105336 10.1016/j.bioorg.2021.105336. [DOI] [PubMed] [Google Scholar]
  15. Devambatla R. K. V.; Choudhary S.; Ihnat M.; Hamel E.; Mooberry S. L.; Gangjee A. Design, synthesis and preclinical evaluation of 5-methyl-N4-aryl-furo[2,3-d]pyrimidines as single agents with combination chemotherapy potential. Bioorg. Med. Chem. Lett. 2018, 28 (18), 3085–3093. 10.1016/j.bmcl.2018.07.039. [DOI] [PubMed] [Google Scholar]
  16. Adams R.; Marvel C. Benzoin. Org. Synth. 2003, 1, 33. 10.1002/0471264180.os001.05. [DOI] [Google Scholar]
  17. Gewald K. Heterocyclen aus CH-aciden Nitrilen, IX. Über die Reaktion von α-Hydroxy-ketonen mit Malodinitril. Chem. Ber. 1966, 99 (3), 1002–1007. 10.1002/cber.19660990340. [DOI] [Google Scholar]
  18. Feng X.; Lancelot J. C.; Prunier H.; Rault S. First synthesis of 4H-furo[3,2-f]pyrrolo[1,2-a][1,4]diazepines. J. Heterocycl. Chem. 1996, 33 (6), 2007–2011. 10.1002/jhet.5570330671. [DOI] [Google Scholar]
  19. Prousek J.; Jurášek A.; Kováč J. Reactions and spectral properties of 2-amino-3-cyano-4,5-disubstituted furane derivatives. Collect. Czech. Chem. Commun. 1980, 45 (5), 1581–1588. 10.1135/cccc19801581. [DOI] [Google Scholar]
  20. Bhuiyan M.; Rahman K. M.; Hossain M.; Rahim M.; Hossain M. Fused Pyrimidines. Part II: Synthesis and Antimicrobial activity of Some Furo[3,2-e]imidazo[1,2-c]pyrimidines and Furo[2,3-d]pyrimidines. Croat. Chem. Acta 2005, 78 (4), 633–636. [Google Scholar]
  21. Taylor E. C.; Loeffler P. K. Studies in Purine Chemistry. IX. A New Pyrimidine Synthesis from o-Aminonitriles. J. Am. Chem. Soc. 1960, 82 (12), 3147–3151. 10.1021/ja01497a042. [DOI] [Google Scholar]
  22. Abdel-Aziz H. A.; Ghabbour H. A.; Eldehna W. M.; Qabeel M. M.; Fun H.-K. Synthesis, Crystal Structure, and Biological Activity of cis/trans Amide Rotomers of (Z)-N′-(2-Oxoindolin-3-ylidene)formohydrazide. J. Chem. 2014, 2014 (1), 760434 10.1155/2014/760434. [DOI] [Google Scholar]
  23. Wyrzykiewicz E.; Prukała D. New isomeric N-substituted hydrazones of 2-, 3-and 4-pyridinecarboxaldehydes. J. Heterocycl. Chem. 1998, 35 (2), 381–387. 10.1002/jhet.5570350221. [DOI] [Google Scholar]
  24. Allam H. A.; Kamel A. A.; El-Daly M.; George R. F. Synthesis and vasodilator activity of some pyridazin-3 (2 H)-one based compounds. Future Med. Chem. 2020, 12 (1), 37–50. 10.4155/fmc-2019-0160. [DOI] [PubMed] [Google Scholar]
  25. Shaker R. M. Synthesis of new furo[2,3-d]pyrimidines and furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines. ARKIVOC 2007, 2006 (14), 68–77. 10.3998/ark.5550190.0007.e10. [DOI] [Google Scholar]
  26. Maruoka H.; Yamagata K.; Yamazaki M. Synthesis of 3-Acyl-5, 6-dihydro-2-phenylthieno (-furo-)[2, 3-d] pyrimidin-4 (3H)-ones. Liebigs Ann. Chem. 1994, 1994 (10), 993–997. 10.1002/jlac.199419941007. [DOI] [Google Scholar]
  27. Farouk A. K.B.A.W.; Abdelrasheed Allam H.; Rashwan E.; George R. F.; Abbas S. E-S. Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors. Bioorg. Chem. 2022, 128, 106099 10.1016/j.bioorg.2022.106099. [DOI] [PubMed] [Google Scholar]
  28. Mohamed T. K.; Batran R. Z.; Elseginy S. A.; Ali M. M.; Mahmoud A. E. Synthesis, anticancer effect and molecular modeling of new thiazolylpyrazolyl coumarin derivatives targeting VEGFR-2 kinase and inducing cell cycle arrest and apoptosis. Bioorg. Chem. 2019, 85, 253–273. 10.1016/j.bioorg.2018.12.040. [DOI] [PubMed] [Google Scholar]
  29. Ahmed E. Y.; Elserwy W. S.; El-Mansy M. F.; Serry A. M.; Salem A. M.; Abdou A. M.; Abdelrahman B. A.; Elsayed K. H.; Abd Elaziz M. R. Angiokinase inhibition of VEGFR-2, PDGFR and FGFR and cell growth inhibition in lung cancer: Design, synthesis, biological evaluation and molecular docking of novel azaheterocyclic coumarin derivatives. Bioorg. Med. Chem. Lett. 2021, 48, 128258 10.1016/j.bmcl.2021.128258. [DOI] [PubMed] [Google Scholar]
  30. Migliozzi M.; Hida Y.; Seth M.; Brown G.; Kwan J.; Coma S.; Panigrahy D.; Adam R. M.; Banyard J.; Shimizu A.; et al. VEGF/VEGFR2 autocrine signaling stimulates metastasis in prostate cancer cells. Curr. Angiogenes 2015, 3 (4), 231–244. 10.2174/221155280304150825120419. [DOI] [Google Scholar]
  31. Modi S. J.; Kulkarni V. M. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: medicinal chemistry perspective. Med. Drug Discovery 2019, 2, 100009 10.1016/j.medidd.2019.100009. [DOI] [Google Scholar]
  32. McTigue M.; Murray B. W.; Chen J. H.; Deng Y.-L.; Solowiej J.; Kania R. S. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (45), 18281–18289. 10.1073/pnas.1207759109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. https://www.rcsb.org/structure/4ASD.
  34. Abraham M. J.; Murtola T.; Schulz R.; Páll S.; Smith J. C.; Hess B.; Lindahl E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015, 1, 19–25. 10.1016/j.softx.2015.06.001. [DOI] [Google Scholar]
  35. Pettersen E. F.; Goddard T. D.; Huang C. C.; Couch G. S.; Greenblatt D. M.; Meng E. C.; Ferrin T. E. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 2004, 25 (13), 1605–1612. 10.1002/jcc.20084. [DOI] [PubMed] [Google Scholar]

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