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. 2023 Dec 12;15(2):416–432. doi: 10.1039/d3md00506b

Role of heterocycles in inhibition of VEGFR-2 – a recent update (2019–2022)

Atukuri Dorababu a,✉
PMCID: PMC10880944  PMID: 38389872

Abstract

The literature reveals that oncogenic protein kinase inhibition has been proved to be a successful anticancer approach. The vascular endothelial growth factor receptor (VEGFR) kinase plays an important role in angiogenesis and metastasis. VEGFR-2 has an upper hand in the angiogenesis process. Vascular endothelial growth factor activates VEGFR-2 which initiates tumor angiogenesis. In addition, VEGFRs are associated with numerous other diseases. Hence, inhibition of VEGFRs is an attractive approach for cancer treatment. In view of this, researchers designed and discovered small molecular heterocycle-based VEGFR-2 inhibitors and some of them have been approved by the Food and Drug Administration (FDA). However, these VEGFR-2 inhibitors pose adverse side effects such as cardiovascular problems, diarrhea, and renal function impairment. Research indicates that combination of certain pharmacophores exhibits excellent VEGFR inhibitory activity. In particular, combination of heterocycles paved the way to efficient VEGFR inhibitors. In this review, the research focusing on VEGFR inhibitory activity has been discussed along with the structure–activity relationship. In addition to emphasizing the most potent molecule among the set of designed molecules, structural features responsible for such an activity are described. This review may aid in designing potent VEGFR inhibitors.

The review describes anti-VEGFR-2 activity of heterocycles including quinazoles, pyrimidines, isatin and azoles considering SAR for a given set of derivatives. Compounds with potent activity were emphasized with description of structural features.graphic file with name d3md00506b-ga.jpg

1. Introduction

VEGFRs are the receptors for vascular endothelial growth factor (VEGF).1,2 VEGFRs are classified into three main subtypes such as VEGFR1, VEGFR2, and VEGFR3. Vascular endothelial growth factors (VEGFs), that are important signaling proteins involved in both vasculogenesis and angiogenesis, bind to VEGFRs on the cell surface causing them to dimerize and become activated. VEGFRs possess an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine kinase domain. VEGFR-2 has been reported to mediate almost all of the known cellular responses to VEGF. Meanwhile, the function of VEGFR-1 is not well defined; however, research reveals that VEGFR-1 modulates VEGFR-2 signaling. The third receptor VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-2. Among these, VEGFR-2 initiates downstream signal transduction leading to angiogenesis, tumor proliferation, and migration.3 Alongside this, activation of VEGFR is associated with poor prognosis of cancer patients.4 Hence, inhibition of VGEFR-2 may be considered as an attractive approach for anti-angiogenesis and anticancer activity.5,6 To date, many small molecule-based VEGFR-2 inhibitors that block signal transduction have been discovered and approved for treatment or entered clinical trials.7 Sunitinib was the first small molecular VEGFR-2 inhibitor to be approved in 2006.8 Various heterocyclic scaffolds such as quinoline and quinazoline derivatives, urea derivatives, indolinone derivatives, and pyridine and pyrimidine derivatives were considered for design and discovery of potent VEGFR-2 inhibitors.7 Some of the approved small molecular VEGFR inhibitors are provided in Fig. 1.9 However, most of the VGEFR-2 inhibitors pose serious side effects in patients such as vascular disturbances and blood vessel regression.10 Hence, researchers are focusing on discovery of efficient VEGFR-2 inhibitors.11

Fig. 1. FDA approved VEGFR inhibitors.9.

Fig. 1

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Therefore, a review of recent literature is essential to understand the developments in VEGFR inhibitors. Particularly the literature of heterocycle-based VEGFR inhibitors published in four years has been discussed along with the structure–activity relationship. Classification of the review was made based on the type of heterocycle. This review might be helpful for future research in bringing out potent VEGFR inhibitors.

1.1. Quinazoline derivatives

Quinazoline derivatives were found to be potent inhibitors of VEGFR. The literature suggests that 4-anilinoquinazolines exhibited kinase inhibitory activity particularly VEGFR.12 In view of this, C. I. Lee et al. have come up with the synthesis and investigation of VEGFR inhibitory activity of triazolyl–quinazoline derivatives.13 Initially, the synthesized compounds were tested for inhibition of Raf (rapidly accelerated fibrosarcoma) kinases. A few compounds that potent activity were investigated for VEGFR-2 inhibition. All the potent Raf kinase inhibitors exhibited excellent VEGFR-2 inhibitory activity. The strongest VEGFR-2 inhibitory activity was noticed for difluorophenyl analog 1 (Fig. 2) with an IC50 value of 0.0070 μM. Meanwhile, compounds 2 and 3 possessing a single fluorine atom rendered slightly reduced activity with IC50 values of 0.012 μM and 0.064 μM, respectively. It was found that the presence of a hydroxy and fluorine substituted phenyl ring produced excellent VEGFR-2 inhibitory activity. However, introduction of a hydroxy group between two fluorine atoms decreased the activity. It might be because of unavailability of the OH group due to steric hindrance. Furthermore, compounds 1–3 showed potent growth inhibitory activity against cancer cell lines PC-9 (prostate cancer-9) and HCC827 (hepatocellular carcinoma).

Fig. 2. Structure of quinazoline–triazole derivatives as potent VEGFR-2 inhibitors [reproduced from ref. 13 with permission from Elsevier, copyright, 2021].

Fig. 2

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Introduction of a sulfonamide moiety at the N-3 position of quinazoline has been reported to increase VEGFR-2 inhibitory activity.14,15 Based on this fact, A. M. Soliman et al. designed a series of molecular hybrids of quinazoline and benzenesulfonamide and investigated them for VEGFR-2 inhibitory activity.16 Initially, the prepared compounds were tested for percentage inhibition against VEGFR-2 wherein a few compounds exhibited potent activity (82.55–90.09%). These compounds were further selected for IC50 value determination against VEGFR-2. Among the few active molecules, compounds 4 and 5 (Fig. 3) were found to be potent inhibitors of VEGFR-2 with IC50 values of 0.48 μM and 0.24 μM, respectively. Compound 5 was found to be as good as the reference sunitinib. The structure–activity relationship reveals that the presence of an alkyl group between the amide group and aromatic ring was favorable for potent VEGFR-2 inhibitory activity.

Fig. 3. Quinazoline–benzene sulfonamides as potent VEGFR-2 inhibitors [reproduced from ref. 16 with permission from Elsevier, copyright, 2019].

Fig. 3

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Evidence suggests that the anilinoquinazoline structure possessed good binding properties for inhibition of the VEGFR-2 kinase.17,18 In addition, based on the efficient VEGFR-2 inhibitory properties of arylamide-containing derivatives, Zhao Y. et al. synthesized arylamide-containing quinazoline derivatives and evaluated them for VEGFR-2 inhibitory activity and anticancer activity.19 Among the evaluated molecules, series of derivatives with a 1,4-aniline linker exhibited better anti-VEGFR-2 activity compared to 1,3-aniline linker analogs. Particularly, 4-fluorophenyl analog 6 (Fig. 4) elicited the strongest anti-VEGFR-2 activity of 101% (IC50 = 64.8 nM). Meanwhile, compounds 7 and 8 presented slightly decreased activity with IC50 values of 734 nM (92.4%) and 372 nM (97.9%), respectively. The SAR indicates that the electron-donating groups at 2- and 3-positions of the phenyl ring rendered diminished activity among the 1,4-aniline linker analogs. Also the 1,4-aniline linker derivatives could show excellent anti-proliferative properties against various cell lines. This fact also proves that linear molecules exhibit good inhibitory potency against the cell lines that overexpress the VEGFR-2 kinase.

Fig. 4. Structure of quinazolines with a 1,4-aniline linker exhibiting potent anti-VEGFR-2 activity [reproduced from ref. 19 with permission from Elsevier, copyright, 2019].

Fig. 4

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R. Wang et al. designed and synthesized hybrids of the 6,7-dimethoxyquinazoline moiety and diarylamide fragments,20,21 in the light of the potent VEGFR-2 inhibitory activity of 6,7-dimethoxyquinazoline and diarylamide containing compounds.22 Most of the tested compounds rendered excellent VEGFR-2 inhibitory activity. Among them, 3-methylphenyl derivative 9 (Fig. 5) demonstrated the strongest activity (IC50 = 16 nM). Change in the position of the methyl group either to the 2- or 4-position diminished the activity. Meanwhile, 3-fluoro (compound 10) and 3-chlorophenyl (compound 11) derivatives showed potent VEGFR-2 inhibitory properties with IC50 values of 47 nM and 75 nM, respectively. Irrespective of their nature, groups present at the phenyl 3-position demonstrated the strongest inhibitory activity.

Fig. 5. 6,7-Dimethoxyquinazoline with diarylamide as VEGFR-2 inhibitors [reproduced from ref. 22 with permission from Elsevier, copyright, 2021].

Fig. 5

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Quinazoline-4-one has been modified by conjugating various key moieties to demonstrate potent VEGFR-2 inhibitory properties.23 All the synthesized molecules were investigated for VEGFR-2 inhibitory activity wherein most of the derivatives exhibited potent activity. Particularly, compound 12 (Fig. 6) elicited the strongest VEGFR-2 inhibitory activity (IC50 = 4.6 μM) and the activity was found to be better than pazopanib. Meanwhile, N-phenyl analog 13 exhibited almost similar activity (IC50 = 4.8 μM), indicating no significant variation in activity with change in substitution on the quinazoline N-atom. Among the two series of derivatives prepared, quinazoline-4-one derivatives with a hydrazide moiety exhibited comparatively better activity than quinazoline analogs with an anilide moiety. In addition, among quinazoline–anilide scaffolds, 5-nitro/5-chloroquinazoline derivatives rendered enhanced activity. Besides, in anti-proliferative activity, compound 12 elicited potent activity with IC50 values of 17.23 μM, 26.10 μM, and 30.85 μM against HepG2 (hepatoblastoma 2), PC3, and MCF-7 (Michigan Cancer Foundation) cell lines, respectively.

Fig. 6. Quinazoline-4-one derivatives with potent VEGFR-2 inhibitory activity [reproduced from ref. 23 with permission from Elsevier, copyright, 2021].

Fig. 6

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Quinazoline has been modified by conjugating thiomethyl ester and a fluorophenyl ring on it to obtain a novel compound.24 The prepared single compound 14 (Fig. 7) was subjected to VEGFR-2 inhibitory activity wherein compound 14 presented excellent activity with an IC50 value of 192 nM. Furthermore, compound 14 could also inhibit cancer cell lines with IC50 values of 1.26 μM, 0.57 μM, and 1.19 μM against HeLa, A549 (Henrietta Lacks) and MDA-MB-231 (MD Anderson Metastatic Breast-231), respectively. The activity against cell lines was far better than that of reference Docetaxel. In addition, docking studies of compound 14 with VEGFR-2 showed a negative value of −5.97 kcal mol−1, indicating the potential inhibitory properties of compound 14 against the VEGFR-2 kinase.

Fig. 7. Structure of quinazoline with thiomethyl ester [reproduced from ref. 24 with permission from Taylor & Francis, copyright, 2021].

Fig. 7

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1.2. Quinoxaline derivatives

Quinoxaline, a bioisostere, is considered as an important nucleus for many anticancer drugs,25,26 and also quinoxaline derivatives were reported to exhibit potent VEGFR-2 inhibitory activity.27,28 Based on these facts, M. M. Alanazi et al. reported 3-methylquinoxaline derivatives as VEGFR-2 inhibitors.29 Initially, the synthesized compounds were investigated for their anticancer activity wherein N-t-butylbenzamide derivative 15 (Fig. 8) rendered the strongest activity with IC50 values of 7.7 μM and 4.5 μM against MCF-2 and HepG2, respectively. Meanwhile, inhibitory activity against VEGFR-2 indicates potent activity by some of the compounds. Among them, compound 15 elicited the highest inhibitory activity (IC50 = 3.2 nM). The activity was found to be as good as that of sorafenib (IC50 = 3.12 nM). The SAR reveals that replacement of the t-butyl group with phenyl derivatives led to decreased VEGFR-2 inhibitory activity. Further, introduction of a hydrazide linker resulted in potent activity. Meanwhile, among thioacetamide analogs, only a few derivatives could show potent activity.

Fig. 8. Structure of the 3-methylquinoxaline derivative with excellent anti-VEGFR-2 activity.29.

Fig. 8

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A new series of quinoxaline-2(1H)-one derivatives were designed and synthesized by K. El-Adl et al.30 as a continuation of their previous work.31,32 All the evaluated molecules rendered excellent VEGFR-2 inhibitory activity. Particularly, compounds 16 and 17 (Fig. 9) demonstrated prominent activity with IC50 values of 1.09 μM and 1.19 μM, respectively. The activity of the above compounds was found to be better than that of the reference sorafenib (IC50 = 1.27 μM). Furthermore, the evaluated molecules were also tested for anticancer activity against various cancer cell lines such as HepG-2, HCT-116 (human colorectal carcinoma-116), MCF-7, and VERO (Verda Rena). It was found that again compounds 16 and 17 presented extraordinary inhibitory values. There is no precise structure–activity relationship that could be established among the evaluated molecules.

Fig. 9. Quinoxalinone derivatives exhibiting efficient VEGFR-2 inhibitory activity [reproduced from ref. 30 with permission from Taylor & Francis, copyright, 2021].

Fig. 9

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1.3. Quinoline derivatives

As reports suggest that the N-methylpiperazinyl moiety showed a positive impact on pharmacokinetics,33 it has been introduced between a thiazole ring and quinazoline-2(1H)-one that can enhance hydrophobic interaction with a hinge region of VEGFR-2 (ref. 34) to obtain a series of piperazinyl derivatives.35 Initially, the synthesized molecules were subjected to anti-proliferative activity wherein moderate-to-excellent activity was noticed. Among them, compounds 18 and 20 demonstrated the strongest activity. Then, in anti-VEGFR-2 activity, most of the molecules showed potent activity. Particularly, compounds 18 and 19 (Fig. 10) rendered noteworthy inhibitory activity with IC50 values of 48.8 nM and 51.09 nM, respectively. Meanwhile, compound 20 exhibited slightly diminished activity (IC50 = 62.7 nM). The VEGFR-2 inhibitory activity of 18 and 19 was found to be as good as that of sorafenib. Combination of quinolinone and the phenyl/4-methoxyphenyl ring proved to be favorable for potent VEGFR-2 inhibitory activity, whereas, in the case of phenyl quinolinone analogs, the presence of the 4-chlorophenyl ring resulted in the most potent activity.

Fig. 10. Structure of piperazinyl derivatives with excellent VEGFR-2 inhibitory activity [reproduced from ref. 35 with permission from Elsevier, copyright, 2021].

Fig. 10

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Owing to the potent c-Met (mesenchymal–epithelial transition factor) kinase inhibitory properties and antitumor activity of thiazolidine-4-one derivatives,36 B. Qi et al. have come up with the design and synthesis of a series of quinoline–thiazolidine-4-one urea derivatives as potent VEGFR-2 inhibitors.37 All the synthesized compounds were initially tested for anticancer activity against various cancer cell lines. Among the various series of quinoline-appended thiazolidinone urea derivatives, dinitrogen heterocyclic ring-containing scaffolds rendered the strongest anticancer activity. The activity was found to be remarkably stronger than the reference cabozantinib. The most potent anticancer agent 21 (Fig. 11) was further investigated for potency against VEGFR-2 inhibitory activity. Surprisingly, compound 21 exhibited excellent VEGFR-2 inhibitory activity (IC50 = 18.7 nM) in addition to inhibition of other kinases. The SAR suggests that replacement of N-methyl piperazine with morpholine reduced the activity a lot indicating that a dinitrogen six-membered ring is essential for potent activity. Besides, attaching a non-fluorophenyl ring to the urea fragment reduced the activity gradually.

Fig. 11. Structure of quinoline–thiazolidine urea derivative [reproduced from ref. 37 with permission from Elsevier, copyright, 2019].

Fig. 11

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1.4. Pyridine/pyrimidine/piperidine derivatives

In the light of selective inhibition of activity of BPS-7 (bronchopulmonary sequestration) against various multiple kinases including VEGFR-2,38 BSP-7 has been modified by introducing 1,2,3-triazole and pyridine pharmacophores to obtain a series of derivatives.39 The inhibitory activity of multiple kinases including VEGFR-2 was performed for the synthesized compounds wherein two compounds excelled. The strongest inhibitory activity against VEGFR-2 was noticed for compound 22 (Fig. 12) with an IC50 value of 1.33 nM. Meanwhile, compound 23 rendered slightly diminished activity with an IC50 value of 1.63 nM. In addition, these two compounds could also show potent inhibitory activity against Tie-2 (tumor infiltrating macrophages). The SAR indicates that the series of derivatives with 2-methoxypyridine demonstrated greater VEGFR-2 inhibitory properties compared to unsubstituted pyridine analogs. Also, conjugation of a highly electron-withdrawing group-substituted phenyl ring on triazole resulted in modest activity.

Fig. 12. Pyridine–triazole derivatives with efficient anti-VEGFR-2 activity [reproduced from ref. 39 with permission from Elsevier, copyright, 2018].

Fig. 12

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Evidence-based establishment of the pyridine nucleus as an antitumor agent40,41 and increasing employment of naphthalene scaffolds in anticancer drug design42,43 inspired Abdelhaleem et al. to design and synthesize a series of naphthalene-containing pyridine derivatives.44 In initial anticancer activity, almost all the evaluated molecules demonstrated excellent activity. Furthermore, the synthesized molecules were tested for inhibition of the VEGFR-2 kinase wherein all the compounds were found to be noteworthy inhibitors. In particular, compounds 24–26 (Fig. 13) elicited the most potent activity with IC50 values of 0.34 nM, 0.25 nM, and 0.19 nM, respectively. Compound 26 with a 3-methoxy-4-hydroxyphenyl ring exhibited the strongest activity, while 4-chlorophenyl derivatives rendered slightly diminished activity. However, 4-nitrophenyl derivative presented twofold reduced activity. This indicated that the VEGFR-2 inhibitory activity increases with the increase in bulkiness of the phenyl ring substitution. A similar trend has also been noticed for other series of derivatives.

Fig. 13. Naphthalene-conjugated pyridine derivatives exhibiting remarkable anti-VEGFR-2 activity [reproduced from ref. 44 with permission from Elsevier, copyright, 2020].

Fig. 13

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In view of the potent anti-tumor activity of the sulfonamide moiety via inhibition of VEGFR-2,45,46 it has been conjugated to a pyridine moiety to obtain a series of molecular hybrids.47 Initially, the synthesized molecules were subjected to growth inhibition of the NCI panel of cancer cell lines. Compound 27 (Fig. 14) demonstrated extraordinary anticancer activity against various cell lines. Hence, it was chosen for inhibition of VEGFR-2 wherein excellent activity was noticed (IC50 = 3.62 μM). The VEGFR-2 inhibitory activity was found to be stronger than that of the reference sorafenib (IC50 = 4.85 μM). The SAR reveals that combination of pyridine with nitrile and amine groups and 3-fluorobenzene produced excellent anticancer activity as well as VEGFR-2 inhibitory activity.

Fig. 14. Pyridine–benzenesulfonamide as a potent anticancer agent and a VEGFR-2 inhibitor [reproduced from ref. 47 with permission from Elsevier, copyright, 2021].

Fig. 14

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Marzouk et al. designed and synthesized 1,6-dihydropyrimidine derivatives considering versatile pharmacology including the antitumor activity of dihydropyrimidine and the NO release activity of oxime.48 The synthesized molecules were tested for in vitro single concentration and five-dose NCI cancer cell line inhibition. Compounds 28 and 29 (Fig. 15) exhibited prominent growth inhibitory activity. Furthermore, these compounds were also evaluated for their VEGFR-2 inhibitory activity wherein remarkable activity was observed with IC50 values of 386.4 nM and 198.7 nM, respectively. The SAR reveals that conversion of ketone to oxime diminished anticancer activity as well as VEGFR-2 inhibitory activity. In addition, unsubstituted phenyl ring or heavily substituted phenyl ring analogs presented stronger pharmacological activity.

Fig. 15. Structure of dihydropyrimidine derivatives with excellent VEGFR-2 inhibitory activity [reproduced from ref. 48 with permission from Elsevier, copyright, 2020].

Fig. 15

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The indole moiety was fused with potent pharmacophore pyrimidine49 considering noteworthy pharmacology including the VEGFR-2 inhibitory activity of pyrimidine–thioindole derivatives.50,51 The prepared molecules were initially investigated for anti-proliferative activity against A549 (hypotriploid alveolar basal epithelial cells), PC-3, MDAMB-231, and HepG2 cell lines. Amongst the evaluated molecules, compounds 30 and 31 (Fig. 16) expressed the strongest anti-proliferative activity against MDAMB-231 cells. Furthermore, all the compounds were subjected to VEGFR-2 inhibitory activity wherein compounds 30 and 31 elicited the strongest activity with IC50 values of 0.31 μM and 0.33 μM, respectively. The SAR shows that introduction of non-aromatic nitrogen heterocycles such as pyrrolidine and piperidine resulted in significant VEGFR-2 inhibitory activity, while compounds with primary amines could only show moderate inhibitory activity. However, strained cyclic amines such as cyclopropyl amine exhibited potent activity. In the case of piperidin-1yl compounds, the presence of the 2,5-dimethylphenyl ring led to the strongest activity. Meanwhile, introduction of a 4-chlorophenyl ring in pyrrolidin-1yl derivatives led to efficient VEGFR-2 inhibitory activity.

Fig. 16. Thioindolyl–pyramidine derivatives with potent VEGFR-2 inhibitory activity [reproduced from ref. 49 with permission from Elsevier, copyright, 2020].

Fig. 16

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N-Aryl piperazine derivatives with potential anticancer activity52,53 have been conjugated to diversified biologically active structural unit chalcone54 to prepare a series of hybrid molecules.55 The synthesized compounds were tested for anticancer activity against the NCI panel of cell lines wherein a few compounds exhibited good-to-excellent activity. Particularly, compounds 32 and 33 (Fig. 17) elicited notable anticancer activity. Further, VEGFR-2 inhibitory activity was determined on the synthesized molecules. The VEGFR-2 inhibitory activity was found to be in line with the anticancer activity. Among them, compounds 32 and 33 presented excellent activity with IC50 values of 0.80 μM and 0.57 μM, respectively. The VEGFR-2 inhibitory activity was found to be more or less similar to that of sorafenib. It is evident from the SAR that the presence of a fluoro group at the 3- or 4-position of the phenyl ring resulted in potent anticancer activity or anti-VEGFR-2 activity. In addition, no improvement of anti-VEGFR-2 activity was observed on cyclization of chalcone into pyrazole.

Fig. 17. Structure of piperazine–chalcone conjugates with potent anti-VEGFR-2 activity.55.

Fig. 17

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1.5. Thiazoles/thiazolidines/thiadiazoles

In the light of the diverse pharmacology of the 1,3,4-thiadiazole moiety,56 it has been utilized to synthesize a series of 1,3,4-thiadiazole–furan carboxamide molecules.57 Some of the synthesized molecules exhibited potent anticancer activity in the initial anticancer screening. Further, potent anticancer molecules were investigated for anti-VEGFR-2 activity. All the evaluated molecules showed promising VEGFR-2 inhibitory activity. In particular, compounds 34 and 35 (Fig. 18) rendered extraordinary activity with IC50 values of 7.4 nM and 7.6 nM, respectively. Introduction of a vinylthiophene moiety did not alter the VEGFR-2 inhibitory activity much. The chloro analog of compound 35 showed reduced activity compared to compound 35 indicating that introduction of a chloro group is unfavorable. Further, transformation of a cyano group into thiazolidinone led to decreased VEGFR-2 inhibitory activity.

Fig. 18. Thiadiazole–furan carboxamide derivatives with extraordinary anti-VEGFR-2 activity [reproduced from ref. 57 with permission from Elsevier, copyright, 2021].

Fig. 18

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Structurally related sulfur and nitrogen molecules thiazolidine–dione derivatives were reported to possess anti-angiogenic activity and VEGFR-2 inhibitory activity.58,59 Khaled El-Adl envisaged the design and synthesis of benzylidenethiazolidine–2,4-dione derivatives.60 Initially, the synthesized compounds were docked with VEGFR-2 wherein stable and favorable interactions with various amino acid residues were observed. In anti-proliferative activity, most of the compounds showed potent activity. Potent anti-proliferative molecules were chosen for VEGFR-2 inhibition. As was observed in anti-proliferative activity, compounds 36–38 (Fig. 19) demonstrated the highest VEGFR-2 inhibitory activity with IC50 values of 0.28 μM, 0.25 μM, and 0.22 μM, respectively. The SAR indicates that generally, derivatives with an anilide moiety connected to benzylanilide or a substituted anilide moiety exhibited potent VEGFR-2 inhibitory activity as well as anticancer activity. In particular, 4-ethylbenzoate molecule 38 presented the highest VEGFR-2 inhibitory activity, while 4-methylbenzene and benzyl analogs rendered slightly reduced activity.

Fig. 19. Illustration of benzylidenethiazolidine–2,4-dione derivatives with anti-VEGFR-2 activity [reproduced from ref. 60 with permission from Elsevier, copyright, 2020].

Fig. 19

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Aziz et al. experimented with bioisosteric modification of sorafenib and sunitinib at four different positions to obtain a series of thiazolidine–2,4-dione derivatives.61 Docking studies were carried out with the synthesized molecules wherein the acetamide linker occupied the same groove occupied by the urea linker of sorafenib indicating its essential role in higher affinity towards VEGFR-2. Also, the presence of furan ring in the derivative exhibited stronger affinity towards VEGFR-2 compared to that of derivatives of thiophene. The VEGFR-2 inhibitory activity of the synthesized molecules revealed that compounds 39–41 (Fig. 20) were the most efficient inhibitors with IC50 values of 80 nM, 83 nM, and 95 nM, respectively, while moderate activity was noticed for furan-connecting thiazolidinone possessing hydrophobic group substituted phenyl rings. Meanwhile, both hydrophobic and hydrophilic groups on the phenyl ring when substituted on thiophene–thiazolidinone scaffolds could also show moderate activity.

Fig. 20. Heterocycle-appended thiazolidinone derivatives with potent anti-VEGFR-2 activity.61.

Fig. 20

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1.6. Isatin/indole derivatives

Considering the beneficial pharmacological properties combined with the low toxicity of indole hydrazone derivatives, Hassan et al. have come up with an idea of linking bromoindole with a substituted phenyl ring through a hydrazole fragment.62 Potent anticancer activity was observed for the synthesized molecules. Meanwhile in anti-VEGFR-2 activity, all the molecules have presented strong anti-VEGFR-2 activity; particularly, compound 42 (Fig. 21) elicited the most potent activity with an IC50 value of 102 nM. The SAR reveals that derivatives with a methyl hydrazone fragment slightly reduced the activity. It was found that the connecting N,N-dimethyl phenyl ring was responsible for the strongest activity of compound 42. In contrast, substitution of bromo, hydroxyl and fluoro phenyl rings exhibited almost twofold reduced activity.

Fig. 21. Bromoindole–hydrazone derivative possessing potent anti-VEGFR-2 activity [reproduced from ref. 62 with permission from John Wiley & Sons, copyright, 2022].

Fig. 21

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The proven potent anticancer activity of 1,2,3-triazoles and isatin derivatives63,64 inspired Wang et al. to design and synthesize a set of derivatives possessing 1,2,3-triazole and isatin moieties.65 Some derivatives rendered excellent anticancer activity against various cancer cell lines. Among those, compounds 43 and 44 (Fig. 22) were the strongest antitumor agents. Meanwhile in VEGFR-2 inhibitory activity, as a coincidence, the potent anticancer agents also proved to be remarkable VEGFR-2 inhibitors. The IC50 values were found to be 26.38 nM and 44.67 nM for compounds 43 and 44, respectively. Furthermore, compound 43 was shown to be the most potent VEGFR-2 inhibitor through docking conformational studies where compound 43 exhibited favorable interactions compared to sunitinib. It was found that substitution of isatin with fluorine resulted in reduced activity. In addition, the potency decreased upon replacement of the methyl group on the phenyl ring with electron-withdrawing groups such as Cl, F, or CN.

Fig. 22. 1,2,3-Triazole–isatin derivatives possessing remarkable anti-VEGFR-2 activity [reproduced from ref. 65 with permission from Elsevier, copyright, 2020].

Fig. 22

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Similar indolinone derivatives were designed and synthesized by W. M. Eldehna et al. based on the core of both sunitinib and nintedanib.66 In this design, the indolinone moiety was linked to pharmacophore diarylurea/diaryamide via a hydrazide linker. In VEGFR-2 inhibitory activity, good-to-moderate activity was noticed. In particular, the strongest VEGFR-2 inhibitory activity was rendered by compound 45 (Fig. 23) with an IC50 value of 0.28 μM. The SAR reveals that irrespective of the nature of the pharmacophore, derivatives with an OCH3 moiety at the 5-position of isatin demonstrated excellent activity. Besides, derivatives with OCH3 at 3-position of terminal phenyl ring of the pharmacophore exhibited potent activity, while change of the position of OCH3 from the 3- to 4-position gradually reduced the activity. However, the strongest inhibitor possessed an OCH3 moiety at both the 5-position of the isatin moiety and the 3-position of the terminal phenyl ring.

Fig. 23. Structure of the most potent VEGFR-2 inhibitor possessing an isatin moiety [reproduced from ref. 66 with permission from Elsevier, copyright, 2019].

Fig. 23

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The potent anticancer activity of isatin and thiazolidine–2,4-dione derivatives inspired Elkaeed et al. to design and synthesize a series of isatin–thiazolidinone derivatives.67 The synthesized molecules were investigated for anticancer activity wherein a few compounds exhibited excellent activity. Potent anticancer molecules were tested for inhibition of the VEGFR-2 kinase. Interestingly, the VEGFR-2 inhibition was in line with the anticancer activity; two isatin derivatives 46 and 47 (Fig. 24) demonstrated remarkable activity with IC50 values of 69.1 nM and 85.8 nM, respectively. Substitution of the methoxy group at the anilide p-position slightly reduced the activity. Meanwhile, quinolinone–thiadizolidinone derivatives showed almost twofold reduced activity, indicating the importance of the isatin moiety.

Fig. 24. Structure of isatin–thiadiazolidinone hybrids with remarkable anti-VEGFR-2 activity.67.

Fig. 24

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Abdelgawad et al. modified isatin by introducing a thiosemicarbazide moiety/an oxadiazolethione ring at the 3-position to obtain a set of isatin derivatives.68 The compounds prepared were evaluated for anticancer properties against various cancer cells. Excellent-to-moderate anticancer properties were noticed. In addition, the synthesized molecules were also subjected to anti-VEGFR-2 activity wherein noteworthy activity was observed for compound 48 (Fig. 25) with an IC50 value of 78 nM. An interesting fact noticed in the SAR is that isatin thiosemicarbazide derivatives showed comparatively better VEGFR-2 inhibitory activity than the cyclic counterparts, insatin–oxadiazolethione derivatives.

Fig. 25. Isatin–thiosemicarbazide derivative with noteworthy anti-VEGFR-2 activity.68.

Fig. 25

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1.7. Fused heterocycles

An almost the same structural framework discussed above has been designed by Atta-Allah et al.69 The synthesized thiadiazole–thiophene molecules were investigated for anticancer activity and then for VEGFR-2 inhibitory activity. The most potent anticancer molecules were subjected to VEGFR-2 inhibitory activity. Although all the tested molecules elicited excellent inhibitory activity, compounds 49 and 50 (Fig. 26) demonstrated remarkable activity in particular with IC50 values of 8.2 nM and 9.4 nM, respectively. Both the compounds were found to be more efficient than pazopanib. The structure–activity relationship indicates that substitution of imine nitrogen with oxygen in compound 50 rendered reduced anticancer activity. In the case of imidazolothiadiazole analogs, the presence of furan was favorable for anticancer activity as well as VEGFR-2 inhibitory activity, while replacement of furan with phenyl derivatives resulted in decreased activity.

Fig. 26. Structures of thiadiazole derivatives with noteworthy anti-VEGFR-2 activity [reproduced from ref. 69 with permission from Elsevier, copyright, 2021].

Fig. 26

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Fused heterocycle triazolothiadiazine was linked to isatin through a hydrazine fragment to obtain a series of novel heterocyclic molecules. All the synthesized molecules were subjected to anticancer activity.70 Initially, anticancer activity reveals strong anticancer properties of the synthesized molecules. Among them, the most potent anticancer agent 51 (Fig. 27) was tested for anti-VEGFR-2 activity. Compound 51 showed VEGFR-2 inhibitory activity (IC50 = 435 nM) close to the reference sunitinib (IC50 = 346 nM).

Fig. 27. Structure of the isatin–triazolothiadiazine derivative.70.

Fig. 27

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Given the remarkable anticancer properties of pyrazole[3,4-d]pyrimidines, a series of pyrazolo[3,4-d]pyrimidine derivatives possessing fused pyrrolidine/piperidine were designed and synthesized by Ruzi et al.71 As was mentioned, the most potent anticancer activity was exhibited by a few synthesized molecules. Specifically, 3,4,5-trimethoxyphenyl analog 52 (Fig. 28) showed elegant inhibitory activity against various cancer cell lines. Further, compound 52 was tested for inhibitory activity against the VEGFR-2 kinase. As expected, compound 52 elicited stronger VEGFR-2 inhibitory activity (IC50 = 13.18 nM) compared to sunitinib (IC50 = 14.2 nM). In addition, favorable interactions and binding energy were observed in docking results of compound 52 with VEGFR-2 kinase.

Fig. 28. Pyrazolo[3,4-d]pyrimidine derivative with strong anticancer and anti-VEGFR-2 activity [reproduced from ref. 71 with permission from Elsevier, copyright, 2022].

Fig. 28

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In view of the potential use of dioxinoquinazoline derivatives as tyrosine kinase inhibitors,72 a series of dihydro[1,4]dioxino[2,3-f] quinazoline analogs were designed and synthesized by D. Wei et al.73 Moderate-to-excellent VEGFR-2 inhibitory properties were noticed for evaluated molecules. Among them, compounds 53–55 (Fig. 29) exhibited the strongest activity with IC50 values of 3.5 nM, 8.8 nM and 3.6 nM, respectively. Meanwhile, 3-chloroaniline analogs showed abated activity. In addition, derivatives with large substituents such as –CF3 exhibited moderate activity. Interestingly, the three compounds possessed a 4-fluoroaniline ring. Alongside this, the most potent molecules 53 and 55 have a 3-fluoroaniline moiety connected to the dioxinoquinazoline pharmacophore. Besides their potent VEGFR-2 inhibitory activity, compounds 53–55 were also found to demonstrate noteworthy anticancer activity against MHCC97H (highly-metastatic hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial cells) cell lines.

Fig. 29. Dioxinoquinazoline derivatives with excellent anti-VEGFR-2 inhibitory activity [reproduced from ref. 73 with permission from Elsevier, copyright, 2019].

Fig. 29

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Research evidence indicates that the urea moiety in many drugs such as lenvatinib exhibits good interactions with VEGFR-2.72 Combining this fact with previous research, H. Fan et al. have come up with designed dioxinoquinazoline derivatives with a urea moiety.74 Most of the evaluated molecules rendered excellent VEGFR-2 inhibitory activity in the nanomolar range. Particularly, compounds 56–58 (Fig. 30) showed the strongest inhibitory activity with IC50 values of 1.48 nM, 1.04 nM, and 2.42 nM, respectively. Derivatives with a 2-fluoro-5-trifluoromethylphenyl moiety demonstrated potent activity, irrespective of other substituents. Furthermore, combination of the 2-fluoro-5-trifluoromethylphenyl moiety with N-propylmorpholine enhanced the VEGFR-2 inhibitory activity. Besides, potent VEGFR-2 inhibitors exhibited efficient anticancer activity.

Fig. 30. Dioxinoquinazoline derivatives with a urea moiety exhibiting potent anti-VEGFR-2 activity [reproduced from ref. 74 with permission from Elsevier, copyright, 2019].

Fig. 30

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Recently identified phthalazine derivatives as efficient anticancer agents75 have been conjugated with pyridazinoquinazoline76 to obtain a series of tricyclic molecules.77 Among those, a few molecules rendered good VEGFR-2 inhibitory activity. In particular, 4-ethoxyaniline analog 59 (Fig. 31) showed the strongest inhibitory activity with an IC50 value of 0.03 μM. The activity of compound 59 was found to be as good as that of sorafenib. Meanwhile, change in the alkyl length in the ethoxy group led to approximately twentyfold decreased activity. 4-Fluoroaniline derivative 60 exhibited potent activity (IC50 = 0.21 μM). However, the 4-chloroaniline derivative demonstrated twofold diminished activity compared to the 4-fluoroaniline analog. In addition, all the compounds were tested for anticancer activity against the HEPG2 cell line wherein compound 60 elicited prominent activity (IC50 = 0.22 μM). The SAR suggests that the aniline moiety with an electron-withdrawing group enhances the VEGFR-2 inhibitory activity as well as anticancer activity.

Fig. 31. Structure of pyridazinoquinazoline derivatives [reproduced from ref. 77 with permission from Elsevier, copyright, 2019].

Fig. 31

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As an extension of their discovery of anticancer agents,78,79 M. M. Alanazi et al. designed and synthesized a series of triazoloquinoxaline derivatives.80 Most of the synthesized molecules exhibited moderate anti-VEGFR-2 activity. Only a few derivatives could show potent activity; particularly compounds 61 and 62 (Fig. 32) demonstrated the strongest VEGFR-2 inhibitory activity with IC50 values of 3.2 μM and 3.1 μM, respectively. Additionally, these molecules were investigated for their anticancer activity wherein compound 61 rendered excellent activity with IC50 values of 3.3 μM and 4.4 μM, against HepG2 and MCF-7, respectively. Meanwhile, compound 62 showed slightly diminished anticancer activity. The anticancer activity was found to be in line with the VEGFR-2 inhibitory activity. The SAR indicates that change in the position of methyl or methoxy groups on the benzene ring decreased VEGFR-2 to a greater extent. Also, introducing a 2-thiazolyl moiety led to the strongest activity revealing that the presence of a heterocycle may enhance VEGFR-2 inhibitory activity as well as anticancer activity.

Fig. 32. Structure of triazoloquinoxaline derivatives exhibiting excellent anti-VEGFR-2 activity [reproduced from ref. 80 with permission from Elsevier, copyright, 2021].

Fig. 32

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As an extension of their work in designing anticancer drugs,81,82 N. A. Alsaif et al. synthesized and designed a series of [1,2,3]triazolo[4,3α]quinoxaline derivatives.83 Almost all the evaluated molecules exerted potent VEGFR-2 inhibitory activity. Particularly, compound 63 (Fig. 33) presented the strongest activity (IC50 = 3.4 nM), while compounds 64 and 65 exhibited slightly diminished activity with IC50 values of 3.9 nM and 4.8 nM, respectively. Among these compounds, 4-chlorophenyl derivative 63 could exhibit anti-VEGFR-2 activity as good as sorafenib. Besides, the synthesized molecules were also tested for anticancer activity wherein compound 63 rendered the most potent activity with IC50 values of 7.2 μM and 4.1 μM against MCF-7 and HepG2, respectively. Although, there is no precise structure–activity relationship, derivatives with a 4-substituted phenyl ring showed moderate activity. Alongside this, modification that involves introduction of a sulfur atom could not achieve potent activity.

Fig. 33. Triazoloquinoxaline derivatives exhibiting noteworthy VEGFR-2 inhibitory activity [reproduced from ref. 83 with permission from Elsevier, copyright, 2021].

Fig. 33

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In view of the potent VEGFR-2 inhibitory activity of recently reported thienopyrimidine derivatives,84,85 S. A. El-Metwally et al. have come up with the design and synthesis of a series of thieno[2,3-d]pyrimidine derivatives.86 Based on the initial anti-proliferative activity, the most potent molecules 66 and 67 (Fig. 34) were chosen for inhibition of VEGFR-2. The VEGFR-2 inhibitory activity of compounds 66 (IC50 = 0.23 μM) and 67 (IC50 = 0.36 μM) was found to be in line with their anti-proliferative activity. The SAR indicates that the chlorobenzene-containing molecule was found to be the most potent VEGFR-2 inhibitor, while the simple phenyl analog resulted in slightly diminished yet potent activity. It was also evident that the molecules were potent when substituted with either a chlorine or nitro group, whereas the presence of both groups led to decreased activity. In addition, substitution of electron-donating groups on the phenyl ring could present reduced activity.

Fig. 34. Illustration of thienopyrimidine derivatives as excellent VEGFR-2 inhibitors [reproduced from ref. 86 with permission from Elsevier, copyright, 2021].

Fig. 34

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A similar structural design with slight modification has been made and a series of thienopyrimidine derivatives were synthesized.87 In the VEGFR-2 inhibitory activity, compounds 68 and 69 (Fig. 35) exhibited the strongest activity with IC50 values of 2.5 μM and 2.27 μM, respectively. Among the pyran-fused thienopyrimidine derivatives, the 3-trifluoromethyl-4-chlorophenyl analog resulted in the highest activity. Change of the urea fragment with thiourea led to deteriorated activity. Also, various substituted phenyl derivatives other than the 3CF3-4F-phenyl analog proved to be inactive against the VEGFR-2 kinase. Meanwhile among the piperidine-fused thienopyrimidine scaffolds, the presence of the thiourea fragment and 4-methoxyphenyl ring showed the most potent activity. Irrespective of substituents on the phenyl ring, urea analogs were found to be inactive.

Fig. 35. Fused thienopyrimidine derivatives exhibiting remarkable anti-VEGFR-2 activity [reproduced from ref. 87 with permission from Elsevier, copyright, 2018].

Fig. 35

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Slightly modified structural analogs indazole derivatives have been reported as excellent VEGFR-2 inhibitors.88 R. M. Hazem et al. utilized this fact in designing benzimidazole derivatives.89 Two molecules 70 and 71 (Fig. 36) were designed which competitively bind to the ATP binding pocket of the VEGFR intracellular domain inhibiting its activity. It can be accomplished by modifying 2-aminopyrimidine of pazopanib. In this study, the imidazole moiety was able to occupy the protein lipophilic pocket and form van der Waals and hydrophobic interactions with key aromatic amino acids. Besides, the hydroxyl group of compound 71 formed a hydrogen bond with Thr916 in the hydrophobic pocket revealing its superiority. Thus, these two compounds disrupt cell proliferation in solid tumors mediated by the VEGFR signaling pathway.

Fig. 36. Structures of benzimidazole derivatives exhibiting VEGFR-2 inhibitory activity [reproduced from ref. 89 with permission from Elsevier, copyright, 2020].

Fig. 36

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1.8. Miscellaneous heterocycles

The literature survey suggests that benzoxazoles are privileged scaffolds for potent antitumor activity as well as VEGFR-2 inhibitory activity.90,91 In the light of this, El-Helby et al. envisaged the synthesis and anti-VEGFR-2 activity of benzoxazole derivatives.92 Some of the synthesized molecules exhibited noteworthy anticancer activity in the initial anticancer screening. Benzoxazole–benzenesulfonamide urea derivatives and benzoxazole–benzenesulfonamide thiourea derivatives could show potent anticancer activity. Further, these molecules were tested for inhibitory activity against VEGFR-2. Among the tested molecules, compounds 72 and 73 (Fig. 37) rendered excellent VEGFR-2 inhibitory activity with IC50 values of 0.08 μM and 0.007 μM, respectively. It was evident from the SAR that replacement of urea with a thiourea moiety has gradually reduced the activity.

Fig. 37. Structures of benzoxazole–benzenesulfonamide urea derivatives with potent anti-VEGFR-2 activity [reproduced from ref. 89 with permission from John Wiley & Sons, copyright, 2019].

Fig. 37

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Pyrazole derivatives witnessed a wide range of pharmacology including potent VEGFR-2 inhibitory activity.93,94 Based on this, Dawood et al. envisaged the design and synthesis of pyrazole derivatives.95 Investigation of inhibitory properties of breast cancer cell lines indicated that the some of the synthesized compounds were excellent anticancer agents. Besides, a remarkable VEGFR-2 inhibitory profile was observed. Interestingly, three compounds 74–76 (Fig. 38) were found to be potent anticancer agents as well as VEGFR-2 inhibitors. The IC50 values of VEGFR-2 inhibitory activity of compounds 74–76 are found to be 0.91 μM, 0.22 μM, and 0.82 μM, respectively. The SAR indicated that replacement of the pyrrolyl moiety with pyridinyl or furanyl moieties resulted in complete abolishment of VEGFR-2 inhibitory activity. Meanwhile, substitution of pyrazoline with an acetyl group at the N-1 position rendered remarkable inhibitory effects. In general, heterocyclic substituents such as pyrrole and furan rings were found to be more favorable for VEGFR-2 inhibitory activity than the six-membered pyridine ring.

Fig. 38. Pyrazole derivatives with excellent anti-VEGFR-2 activity [reproduced from ref. 95 with permission from John Wiley & Sons, copyright, 2020].

Fig. 38

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2. Discussion and conclusion

As discussed earlier, cancer is one of the most devastating diseases. Cancer prevails in the body by the process of angiogenesis. Vascular endothelial growth factors are responsible for formation of new blood vessels in tumors thereby involving metastasis. Hence, inhibition of VEGFRs is a scientific approach to treat cancer. The literature reveals that heterocyclic small molecules were found to be promising in VEGFR-2 inhibition. A review of heterocycle-based VEGFR-2 inhibitory activity was accomplished. Quinazolines attached to 1,2,3-triazole amides as well as arylurea derivatives witnessed excellent (nanomolar activity) activity among the quinazoline derivatives. Meanwhile, attaching sulfonamide to quinazolinones rendered moderate activity. Further, conjugation of a diaminophenol moiety resulted in potent activity. In the case of quinoxaline analogs, fusion of triazole could only bring moderate activity, whereas attaching arylamides via an acetamide linker achieved nanomolar activity. Besides, linear pyridine derivatives of 1,2,3-triazoles exhibited efficient VEGFR-2 inhibitory activity. Efficiency was increased with pyridine hydrazine possessing a naphthalene moiety. Contrary to this, inclusion of benzenesulfonamide showed moderate activity. Then, pyrimidine derivatives failed to exhibit potent activity. Regardless of substitution, piperazine derivatives showed good VEGFR-2 inhibitory properties. In the case of five-membered heterocyclic compounds, thiadiazoles connected to furan/thiophene/piperazine rendered the strongest activity, whereas thiazole analogs without any heterocycle connected could not show potent activity. In addition, heterocyclic compounds such as benzoxazole–benzenesulfonamides and 1,2,3-trizole–isatin derivatives were also successful in exhibiting remarkable VEGFR-2 inhibitory activity.

3. Future perspectives

Observation of heterocyclic compounds with corresponding VEGFR-2 inhibitory activity reveals that the presence of two or more heterocycles in a drug molecule is an efficient drug design approach. In particular, inclusion of an arylurea moiety, 1,2,3-triazole or furan has an attractive pharmacological effect. Further, pyridine and piperazine moieties could be instrumental in designing potent VEGFR-2 inhibitors/anticancer agents.

Conflicts of interest

There are no conflicts of interest.

Supplementary Material

Biography

Atukuri Dorababu.

Atukuri Dorababu

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Dr. Atukuri Dorababu obtained his MSc (2010) and PhD (2017) in Chemistry from Karnatak University, Dharwad. He worked as a research associate at Syngene, Bengaluru, for a short period. Later, he worked as a lecturer in Chemistry for five years (2013–2017) at Govt. Pre-University College, Belgaum. Later in 2017, he was appointed as an assistant professor at SRMPP GFGC, Huvinahadagali, and is presently working there in the same position. He has around 33 publications in various reputed international journals. His research focused on drug discovery, enzyme inhibition, anti-microbial activity, anticancer activity, anti-Alzheimer, extraction of natural products and their pharmacological activity.

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