Recent Advancements in the Development of Anti-Breast Cancer Synthetic Small Molecules

Among all cancer types, breast cancer (BC) still stands as one of the most serious diseases responsible for a large number of cancer-associated deaths among women worldwide, and diagnosed cases are increasing year by year worldwide. For a very long time, hormonal therapy, surgery, chemotherapy, and radiotherapy were used for breast cancer treatment. However, these treatment approaches are becoming progressively futile because of multidrug resistance and serious side effects. Consequently, there is a pressing demand to develop more efficient and safer agents that can fight breast cancer belligerence and inhibit cancer cell proliferation, invasion and metastasis. Currently, there is an avalanche of newly designed and synthesized molecular entities targeting multiple types of breast cancer. This review highlights several important synthesized compounds with promising anti-BC activity that are categorized according to their chemical structures.


Introduction
Worldwide, breast cancer is the most prevalent cancer and the second type of cancer leading to mortality in women [1]. More than 276,480 new breast cancer cases are expected to be identified in women in the United States in 2020 [2]. Risk factors linked to breast cancer continue to be identified [3]. Accordingly, breast cancer is considered one of the urgent public health problems globally [4].
Breast cancer is promoted via different types of factors (endogenous and exogenous) which have differing outcomes [5]. Treatment of invasive BC is quite challenging due to its aggressive features [6,7]. A plentiful body of evidence suggests that long-term survival can be increased, if there is an ability to suppress distant metastasis [8,9]. Breast cancer treatment depends on a mechanism(s) that can be targeted by natural or synthetic compounds that already exist as antitumor drugs [10,11]. Not surprisingly, literature reviews revealed that many heterocyclic and/or other scaffolds have been developed as anti-breast cancer agents [12][13][14].

Different Subtypes of Breast Cancer
There are four main subtypes of female breast cancer [15] (Figure 1): Luminal A: This group has tumors that are estrogen-receptor and/or progesterone-receptor positive (+ve ER and/or +ve PR), but it is human epidermal growth factor receptor negative The BC subtype HR+/HER2− (HR+ stands for BC cells possessing receptors for the hormones estrogen or progesterone) has been identified as the most common subtype with a rate of 85.8 new cases per 100,000 women, according to 2012-2016 cases. This is a There are six subtypes of basal-like breast cancer reported by Lehmann et al. [16] which are treated differently [17]: basal-like 1 (BL1), basal-like 2 (BL2), Immunomodulatory (IM), Mesenchymal (M), Mesenchymal stem like (MSL), Luminal androgen receptor (LAR).
The BC subtype HR+/HER2− (HR+ stands for BC cells possessing receptors for the hormones estrogen or progesterone) has been identified as the most common subtype with a rate of 85.8 new cases per 100,000 women, according to 2012-2016 cases. This is a rate more than 6-fold higher than the TNBC rate of 13.0 and the HR+/HER2+ BC rate of 12.9, and over 15-fold higher than HR−/HER2+ BC rate of 5.4.

Pertuzumab
Pertuzumab is a recombinant humanized monoclonal antibody that targets HER2positive BC which can inhibit the proliferation of human tumor cells [30]. The most common side effects of Pertuzumab include hair loss, low white blood cell count, rash, diarrhea, fatigue, nausea, and peripheral neuropathy (tingling in hands and feet and numbness) [40].

Alpelisib
Alpelisib ( Figure 2) is a phosphatidylinositol 3-kinase (PI3K) inhibitor that impedes the growth of tumor cells. Alpelisib is used in combination with fulvestrant (Faslodex ® ) for treatment of postmenopausal women with a certain type of metastatic BC [41].

Talazoparib
Talazoparib (Talzenna ® , Figure 2) belongs to a class of drugs called PARP inhibitors used for treatment of local advanced or metastatic HER2-negative BC women with a BRCA1 or BRCA2 mutation [42].

Anastrozole
Anastrozole ( Figure 2) is a reversible, nonsteroidal inhibitor of the aromatase enzyme that is taken orally. Anastrozole is an essential anticancer drug that is indicated as an adjuvant remedy in the treatment of HR+ BC in postmenopausal women at early stages [36].

Ixabepilone
Ixabepilone (Figure 2), a semisynthetic analog of epothilone B, stabilizes the microtubules which are essential for cell division via suppression of the dynamic of microtubules (aβ-II and aβ-II). Hence, it arrests the cell cycle in the G2-M phase, induces tumor cell apoptosis and inhibits tumor cell proliferation. In 2007, Ixabepilone was granted an FDA approval for the treatment of patients with locally advanced or aggressive metastatic BC [37].

Fulvestrant
Fulvestrant ( Figure 2) is a synthetic estrogen receptor and an aromatase inhibitor. It decreases the amount of estrogen in the BC cells through binding to estrogen receptors which leads to estrogen receptor deformation [38].

Pertuzumab
Pertuzumab is a recombinant humanized monoclonal antibody that targets HER2positive BC which can inhibit the proliferation of human tumor cells [30]. The most common side effects of Pertuzumab include hair loss, low white blood cell count, rash, diarrhea, fatigue, nausea, and peripheral neuropathy (tingling in hands and feet and numbness) [40].

Alpelisib
Alpelisib ( Figure 2) is a phosphatidylinositol 3-kinase (PI3K) inhibitor that impedes the growth of tumor cells. Alpelisib is used in combination with fulvestrant (Faslodex ® ) for treatment of postmenopausal women with a certain type of metastatic BC [41].

Talazoparib
Talazoparib (Talzenna ® , Figure 2) belongs to a class of drugs called PARP inhibitors used for treatment of local advanced or metastatic HER2-negative BC women with a BRCA1 or BRCA2 mutation [42].

Quinoline-Based Small Molecules
The great advances in the azaheterocyclic synthesis in the last decades allowed the synthesis of different quinoline derivatives. Recently, Viswas et al. reported the synthesis of two new sets of piperazinyl-quinoline derivatives bearing urea or thiourea functionalities based on the reaction of 4-(piperazin-1-yl)quinoline 3a-b with isocyanate or thiocyanate derivatives. The synthesized quinolines were screened for their anti-proliferative activity against BC cell lines. The results highlighted that quinoline derivative 4 ( Figure 3) possessed potent activity against MDA-MB-231 (GI 50 = 3.0 ± 0.1 µM), while quinoline derivative 5 ( Figure 3) exhibited improved anti-proliferative impact towards MDA-MB468 and MCF-7 (GI 50 = 2.7 ± 0.1 and 2.0 ± 0.1µM, respectively) [43]. Most recently, Patel et al. [48] identified a novel class of 3-phenyltrifluorom quinoline derivatives ( Figure 3) and determined their anti-proliferative potential tow the breast cancer MCF-7 cell line. Among the synthesized derivatives, compoun displayed the highest anticancer activity with growth inhibition value in the nanom range (GI50 = 4 nM). The performed molecular docking analysis in this study sug thymidine phosphorylase as a plausible target for the prepared 3-phenyltrifluorom quinolines [48].
Moreover, Bheemanapalli et al. [45] described the synthesis and anticancer activity evaluation of a new set of dihydroquinoline derivatives 10 and 11 ( Figure 3). Preliminary screening revealed that compounds 10a-d demonstrated potent growth inhibitory potential against breast cancer MCF-7 cell line compared to the reference drug. In addition, compound 11 ( Figure 3) showed a significant growth inhibitory potential against three breast cancer cell lines: T47D, MCF-7 and MDA-MB-231, with IC 50 values equal 2.20 ± 1.5, 3.03 ± 1.5 and 11.90 ± 2.6 µM, respectively [46].
Moustafa et al. [47] synthesized a novel series of 2-quinolinone derivatives and evaluated their anti-proliferative activity against the BC MCF-7 cell line. The results revealed that compounds 12 and 13 ( Figure 3) elicited the highest anti-proliferative activity. Moreover, these compounds cause induction of apoptosis at pre-G1 phase, beside cell cycle arrest (G2/M) phases. Most recently, Patel et al. [48] identified a novel class of 3-phenyltrifluoromethyl quinoline derivatives ( Figure 3) and determined their anti-proliferative potential toward the breast cancer MCF-7 cell line. Among the synthesized derivatives, compound 14 displayed the highest anticancer activity with growth inhibition value in the nanomolar range (GI 50 = 4 nM). The performed molecular docking analysis in this study suggests thymidine phosphorylase as a plausible target for the prepared 3-phenyltrifluoromethyl quinolines [48].

Quinazoline-and Quinazolinone-Based Small Molecules
Several quinazoline and quinazolinone derivatives have been synthesized and reported for their anti-breast cancer activity. In 2016, Yin et al. reported the design and synthesis of a novel set of oxazolo-quinazoline derivatives ( Figure 4) as dual inhibitors of EGFR/HER2. Among the synthesized compounds, 18-21 revealed significant inhibition for EGFR and HER2. Furthermore, compound 21 showed excellent anti-proliferation activity against the SKBr-3 cell line with IC 50 = 0.47 ± 0.35 µM, compared to the reference drug Lapatinib (Table 1, Figure 4) [49].    Additionally, Ahmed et al. [50] discovered a new series of quinazolin-4-one derivatives and screened them against EGFR tyrosine kinase, as well as against the MCF-7 cell line. Compound 22 (Figure 4) revealed good EGFR inhibitory activity and powerful cytotoxic activity toward the tested MCF-7 cell line.
Furthermore, another novel series of quinazolin-4(3H)-one derivatives were designed, prepared and evaluated as anti-breast cancer agents [51], where compounds 23 and 24 ( Figure 4) showed the highest activity against the MCF-7 cell line. Moreover, two new synthetic ellipticine analogs 25 and 26 ( Figure 4) were designed and synthesized. Both compounds showed an elegant anti-proliferative effect for the MCF-7 cell line, with IC 50 equal to 6.246 µmol/L and 5.910 µmol/L, respectively. Additionally, the two molecules were proven to induce intrinsic and extrinsic apoptosis at the cellular level [52].
Recently, Wang et al. developed a new 4-aminoquinazoline derivative 27 (Figure 4), and verified that it suppressed the proliferation, growth, migration, and invasion of human breast cancer cells. This was proven to occur via inhibiting the signaling pathway of PI3K/AKT/mTOR in vitro and in vivo with considerable safety profile [53].

Pyridine and Fused Pyridine Derivatives
Most recently, Khalili et al. reported the design and synthesis of a new series of styrylimidazo[1,2-a]pyridine derivatives 30 ( Figure 5) via reaction of cinnamaldehydes, 2-aminopyridines, and cyclohexyl/tert-butyl isocyanide mixture (Bienayme reaction). The synthesized compounds were screened against three breast cancer cell lines: MDA-MB-231, MCF-7, and T-47D using MTT assay. Most of the tested compounds displayed higher activity compared to the reference drug, etoposide. Fortunately, compound 30a ( Figure 5) showed the highest activity against the three examined breast cancer cell lines with IC 50 values of 12.12 ± 0.54 µM, 9.59 ± 0.7 µM and 10.10 ± 0.4 µM, respectively. It is worth mentioning that the cytotoxic activity of the prepared styrylimidazo[1,2-a]pyridine derivatives is attributable to their ability to provoke apoptosis in the examined BC cell lines [54].
Furthermore, Prasad et al. developed novel pyridine-bearing phosphonate esters 32 ( Figure 5) as potential aromatase inhibitors. The design of these derivatives was performed utilizing computational docking analysis studies which revealed their ability to form strong H-bonds with the essential amino acid residues in the enzyme active site with considerable low energy. Accordingly, this serves as the mechanistic explanation for the significant in vitro cytotoxic activity observed by the compounds against the MCF-7 breast cancer cell line [56].
As a continuous search for novel potent anti-breast cancer agents, Rahnamay et al. reported the design and synthesis of a novel series of pyranopyridine derivatives. The antiproliferative screening of the synthesized compounds identified compound 33 ( Figure 5) as an effective cytotoxic agent against the MCF-7 cell line, with an IC 50 value of 60 µM. Further cell cycle analysis, A.O./Et.Br. double staining and DNA fragmentation assay proved that compound 33 exerted its anti-proliferative activity by apoptosis induction in MCF-7 cells [57].  Figure 5) as potential aromatase inhibitors. The design of these derivatives performed utilizing computational docking analysis studies which revealed their a to form strong H-bonds with the essential amino acid residues in the enzyme activ with considerable low energy. Accordingly, this serves as the mechanistic explanati the significant in vitro cytotoxic activity observed by the compounds against the M breast cancer cell line [56].

Pyridazine-Based Small Molecules
In 2020, Sabt et al. designed and synthesized a new series of 3,6-disubst pyridazines ( Figure 6) as promising antitumor agents targeting cyclin-dependent k 2 (CDK-2). Furthermore, the target 3,6-disubstituted pyridazines were in vitro eval for their growth inhibitory activity against three human cancer cell lines. The r showed that the compounds displayed selective cytotoxic activity against breast c cell lines, MDA-MB-231 and T-47D, while they revealed weak activity against ov cancer cell line SKOV-3. Among all these derivatives, compound 34 ( Figure 6 grasped as a potent cytotoxic agent against MDA-MB-231 and T-47D, with IC50 valu 0.99 ± 0.03 and 0.43 ± 0.01 μM, respectively [58]. Previously, Kim et al. developed a new series of 3-alkylamino-6-allylthio-pyrid derivatives by using 3,6-dichloropyridazine as starting material and were evalua cytotoxicity assays. Among these, compounds 35 and 36 ( Figure 6) revealed h potencies against the MCF-7 cell line compared to the standard drug 5FU with IC50 v of 17.2 μg/mL, 17.16 μg/mL and 477.47 μg/mL, respectively [59]. Moreover, the au prepared another series from 3-allylseleno-6-alkylthiopyridazines to investigate biological activity as anti-breast cancer agents. For the derivatives tested, 3-allylsele

Pyridazine-Based Small Molecules
In 2020, Sabt et al. designed and synthesized a new series of 3,6-disubstituted pyridazines ( Figure 6) as promising antitumor agents targeting cyclin-dependent kinase 2 (CDK-2). Furthermore, the target 3,6-disubstituted pyridazines were in vitro evaluated for their growth inhibitory activity against three human cancer cell lines. The results showed that the compounds displayed selective cytotoxic activity against breast cancer cell lines, MDA-MB-231 and T-47D, while they revealed weak activity against ovarian cancer cell line SKOV-3. Among all these derivatives, compound 34 ( Figure 6) was grasped as a potent cytotoxic agent against MDA-MB-231 and T-47D, with IC 50 values of 0.99 ± 0.03 and 0.43 ± 0.01 µM, respectively [58].
Previously, Kim et al. developed a new series of 3-alkylamino-6-allylthio-pyridazine derivatives by using 3,6-dichloropyridazine as starting material and were evaluated in cytotoxicity assays. Among these, compounds 35 and 36 ( Figure 6) revealed higher potencies against the MCF-7 cell line compared to the standard drug 5FU with IC 50 values of 17.2 µg/mL, 17.16 µg/mL and 477.47 µg/mL, respectively [59]. Moreover, the authors prepared another series from 3-allylseleno-6-alkylthiopyridazines to investigate their biological activity as anti-breast cancer agents. For the derivatives tested, 3-allylseleno-6-pentylthiopyridazine 37 ( Figure 6) exhibited the highest cytotoxic activity compared to 5FU against the MCF-7 cell line [60]. On the other hand, a new series of arylpyridazines was designed, synthesized and studied as anti-proliferative agents against seven cancer cell lines: HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727 and HaCaT. Compound 38 ( Figure 6) displayed favorable potent activity against all the tested cell lines with an IC 50 value of 0.1 µM. Further mechanistic investigations revealed the ability of the target pyridazine derivatives to affect p44/42 and Akt-dependent signaling pathways [61]. pentylthiopyridazine 37 ( Figure 6) exhibited the highest cytotoxic activity compared to 5FU against the MCF-7 cell line [60]. On the other hand, a new series of arylpyridazines was designed, synthesized and studied as anti-proliferative agents against seven cancer cell lines: HuH7, CaCo-2, MDA-MB-231, HCT116, PC3, NCI-H727 and HaCaT. Compound 38 ( Figure 6) displayed favorable potent activity against all the tested cell lines with an IC50 value of 0.1 μM. Further mechanistic investigations revealed the ability of the target pyridazine derivatives to affect p44/42 and Akt-dependent signaling pathways [61].

Non-Fused and Fused Pyrimidines Moiety
Surveying the literature revealed that the pyrimidine entity serves as a promising scaffold for designing potent anti-breast cancer agents [62]. Accordingly, new derivatives of thieno[2,3-d]pyrimidine were synthesized and screened against MCF-7 breast cancer cell line. The results displayed that compound 42 ( Figure 7) showed the most cytotoxic activity against breast cancer cell line MCF-7 with low IC50 with significant safety margin against non tumerogenic MCF-10A cell line. Further in vitro studies disclosed that the aforementioned compound exerts its cytotoxic activity through inhibition of pim-1 kinase [63].
In 2019, Wang et al. reported the design and synthesis of a series of isolongifoleno pyrimidine derivatives through three steps using fragment-based design approach. The anti-proliferative effect against breast cancer MCF-7 cell was estimated. Among all the tested pyrimidine derivatives, compound 45 ( Figure 7) bearing 4-fluorophenyl and 4methylphenyl moieties displayed maximum cytotoxic activity with IC50 value of 0.33 + 0.24 μM. Moreover, compound 45 was proven to induce apoptosis in the aforementioned cancer cells by boosting ROS generation [64].
Moreover, new compounds of camphor-based pyrimidine derivatives were synthesized and studied for their anticancer activity against three cancer cell lines: MDA-MB-231, A549 and RPMI-8226. According to the results of cytotoxicity assays, compound 48 ( Figure 7) possessed the most potent cytotoxic activity against the tested cancer cell lines compared to the reference drug etoposide with much lower cytotoxic effect against normal cell GES-1 (IC50 > 50 μM vs. 8.89 μM). Noteworthy, the cytotoxic activity of compound 48 was attributable to the ROS-mediated mitochondrial apoptosis [65]. In

Non-Fused and Fused Pyrimidines Moiety
Surveying the literature revealed that the pyrimidine entity serves as a promising scaffold for designing potent anti-breast cancer agents [62]. Accordingly, new derivatives of thieno[2,3-d]pyrimidine were synthesized and screened against MCF-7 breast cancer cell line. The results displayed that compound 42 ( Figure 7) showed the most cytotoxic activity against breast cancer cell line MCF-7 with low IC 50 with significant safety margin against non tumerogenic MCF-10A cell line. Further in vitro studies disclosed that the aforementioned compound exerts its cytotoxic activity through inhibition of pim-1 kinase [63].
In 2019, Wang et al. reported the design and synthesis of a series of isolongifoleno pyrimidine derivatives through three steps using fragment-based design approach. The anti-proliferative effect against breast cancer MCF-7 cell was estimated. Among all the tested pyrimidine derivatives, compound 45 ( Figure 7) bearing 4-fluorophenyl and 4-methylphenyl moieties displayed maximum cytotoxic activity with IC 50 value of 0.33 + 0.24 µM. Moreover, compound 45 was proven to induce apoptosis in the aforementioned cancer cells by boosting ROS generation [64].
Moreover, new compounds of camphor-based pyrimidine derivatives were synthesized and studied for their anticancer activity against three cancer cell lines: MDA-MB-231, A549 and RPMI-8226. According to the results of cytotoxicity assays, compound 48 ( Figure 7) possessed the most potent cytotoxic activity against the tested cancer cell lines compared to the reference drug etoposide with much lower cytotoxic effect against normal cell GES-1 (IC 50 > 50 µM vs. 8.89 µM). Noteworthy, the cytotoxic activity of compound 48 was attributable to the ROS-mediated mitochondrial apoptosis [65].
In  Figure 7) exhibited significant cytotoxic activity against the MDA-MB-231 TNBC cancer cell line. Moreover, it proved to be a potent multikinase inhibitor against Src with an IC 50 value in the nanomolar range (0.9 nM), and against MAPK signaling protein kinases including B-RAF and C-RAF. Compound 49 also was proven to provoke apoptosis in the examined cancer cell line [66].
A series of pyrimidine Nand S-glycosides incorporating an oleyl residue were synthesized and evaluated against two cancer cell lines (MCF-7 and HepG2). The assay results outputs revealed that the tested compounds displayed moderate to high activities. Moreover, compounds 50 and 51 ( Figure 7) exhibited the most potent activity against MCF-7 and HepG2 cancer cell lines with IC 50 value of 13.2 µM and 24.9 µM, and 22.6 µM and 16.2 µM, respectively [67].  A series of pyrimidine N-and S-glycosides incorporating an oleyl residue were synthesized and evaluated against two cancer cell lines (MCF-7 and HepG2). The assay results outputs revealed that the tested compounds displayed moderate to high activities. Moreover, compounds 50 and 51 ( Figure 7) exhibited the most potent activity against MCF-7 and HepG2 cancer cell lines with IC50 value of 13.2 μM and 24.9 μM, and 22.6 μM and 16.2 μM, respectively [67].
Moreover, a novel thienopyrimidine derivative (52) (Figure 7) was designed and synthesized as a VEGFR-2 tyrosine kinase inhibitor, a potential activity target of breast cancer. Thienopyrimidine 52 showed potent activity against T47D (IC50 = 6.9 ± 0.04 μM) and MDA-MB-231 (IC50 = 10 ± 0.04 μM). Additionally, compound 52 significantly inhibited VEGFR-2 by a percentage of 65%, and it down-regulated the level of VEGF in the MCF-7 cancer cell line by 30.4% which explained the molecular basis of the observed antiproliferative activity [68]. Moreover, a novel thienopyrimidine derivative (52) (Figure 7) was designed and synthesized as a VEGFR-2 tyrosine kinase inhibitor, a potential activity target of breast cancer. Thienopyrimidine 52 showed potent activity against T47D (IC 50 = 6.9 ± 0.04 µM) and MDA-MB-231 (IC 50 = 10 ± 0.04 µM). Additionally, compound 52 significantly inhibited VEGFR-2 by a percentage of 65%, and it down-regulated the level of VEGF in the MCF-7 cancer cell line by 30.4% which explained the molecular basis of the observed antiproliferative activity [68]. activities compared to the reference drug (5-FU and irinocam) against the aforementioned cancer cell line giving insight that this scaffold can serve as a good platform for designing novel anti-breast cancer agents [70]. Moreover, new benzoimidazole derivatives 63 ( Figure 8) were designed and synthesized to explore their anti-proliferative activity. In particular, compound 63a (Figure 8) exhibited the highest anticancer activity (IC50 = 0.0047 μM/mL) against the MCF-7 cancer cell line with almost equal cytotoxicity compared to the reference drug tamoxifen [71].  The imidazole derivatives 60a-c ( Figure 8) were synthesized through a condensation reaction between phenylglyoxal monohydrate with guanidnyl hydrazone. All target imidazoles were screened for human breast cancer cell line MCF-7 by using the MTT assay. Results showed that compounds 60a-b ( Figure 8) revealed higher cytotoxic activities compared to the reference drug (5-FU and irinocam) against the aforementioned cancer cell line giving insight that this scaffold can serve as a good platform for designing novel anti-breast cancer agents [70]. Moreover, new benzoimidazole derivatives 63 ( Figure 8) were designed and synthesized to explore their anti-proliferative activity. In particular, compound 63a (Figure 8) exhibited the highest anticancer activity (IC 50 = 0.0047 µM/mL) against the MCF-7 cancer cell line with almost equal cytotoxicity compared to the reference drug tamoxifen [71].

Imidazole and Benzimidazole Derivatives
Mohan et al. [72] synthesized new compounds based on imidazole scaffold as anti-BC agents through inhibition of the signaling pathway of PI3K/Akt/mTOR. Anticancer results revealed that compound 64 ( Figure 8) demonstrated potent activity against two breast cancer cell lines, MDA-MB-231 and MCF-7. Additionally, a novel series of imidazole-isatinthiosemicarbazone and 1,2,3-triazole tethered imidazole-isatin hybrids were designed, synthesized and studied as anti-breast cancer agents ( Figure 8). It was found that compound 65 was the most potent counterpart with the value of IC 50

Coumarin Derivatives
Ahmed et al. designed and synthesized twenty-five coumarin-based derivatives and evaluated their anti-proliferative activity against the MCF-7 cancer cell line and their VEGFR-2 kinase inhibitory activity. Compounds 68 and 69 ( Figure 9) displayed a maximal significant response against the MCF-7 cancer cell line with an IC 50 value of 1.24 µM and 1.65 µM, respectively, comparable to that of the reference drug staurosporine (IC 50 = 8.81 µM). Furthermore, compound 68 was able to inhibit VEGFR-2 kinase activity at an IC 50 of 0.36 µM which is comparable for that recorded by staurosporine (IC 50 = 0.33 µM) [75].
were designed, synthesized and studied as anti-breast cancer agents (Figure 8). It was found that compound 65 was the most potent counterpart with the value of IC50 26.12 μM and 54.25 μM against MDA-MB-231 and MCF-7 cell lines, respectively [73].

Coumarin Derivatives
Ahmed et al. designed and synthesized twenty-five coumarin-based derivatives and evaluated their anti-proliferative activity against the MCF-7 cancer cell line and their VEGFR-2 kinase inhibitory activity. Compounds 68 and 69 ( Figure 9) displayed a maximal significant response against the MCF-7 cancer cell line with an IC50 value of 1.24 μM and 1.65 μM, respectively, comparable to that of the reference drug staurosporine (IC50 = 8.81 μM). Furthermore, compound 68 was able to inhibit VEGFR-2 kinase activity at an IC50 of 0.36 μM which is comparable for that recorded by staurosporine (IC50 = 0.33 μM) [75]. The condensation reactions of 4-hydroxycoumarin, aldehydes and cyclic secondary amines yielded the bis-coumarins derivatives 73 and 74 ( Figure 9). A cytotoxicity of the novel coumarin derivatives against the MCF-7 breast cancer cell line was evaluated and displayed that compound 73 has a promising cytotoxic activity against MCF-7 with an IC50 value of 12.1 μg/mL which is superior to that of the reference drug doxorubicin with an IC50 value of 16.2 μg/mL. A molecular docking study for the target compounds identified Topoisomerase IIa as a potential target [76].
New compounds of fluorinated coumarin-based derivatives were synthesized, and their anti-proliferative activity was studied on MCF-7 and HeLa in addition to their potential to inhibit VEGFR-2. Compounds 75, 76 and 77 ( Figure 9) exhibited higher inhibition activity against the MCF-7 cell line (IC50 = 8.30 μg/mL, 8.28 μg/mL, and 7.90 μg/mL, respectively). Furthermore, these coumarins unveiled superior inhibitory activity The condensation reactions of 4-hydroxycoumarin, aldehydes and cyclic secondary amines yielded the bis-coumarins derivatives 73 and 74 ( Figure 9). A cytotoxicity of the novel coumarin derivatives against the MCF-7 breast cancer cell line was evaluated and displayed that compound 73 has a promising cytotoxic activity against MCF-7 with an IC 50 value of 12.1 µg/mL which is superior to that of the reference drug doxorubicin with an IC 50 value of 16.2 µg/mL. A molecular docking study for the target compounds identified Topoisomerase IIa as a potential target [76].

Tetrazole-Bearing Derivatives
Dileep and coworker described a novel series of tetrazole-bearing ciprofloxacin and pipemidic acid derivatives and screened their anti-proliferative activity against the MDA-MB-231 breast cancer cell line. Based on the results assay, compounds 79a-b and 80a-b ( Figure 10) displayed the most potent cytotoxic activity with growth inhibition ranging (GI 50 = 0.08-0.09 µM), which is significantly more potent than the reference drug tamoxifen (GI 50 = 0.24 µM) against the MDA-MB-231 cell line [79].

Tetrazole-Bearing Derivatives
Dileep and coworker described a novel series of tetrazole-bearing ciprofloxacin and pipemidic acid derivatives and screened their anti-proliferative activity against the MDA-MB-231 breast cancer cell line. Based on the results assay, compounds 79a-b and 80a-b ( Figure 10) displayed the most potent cytotoxic activity with growth inhibition ranging (GI50 = 0.08-0.09 μM), which is significantly more potent than the reference drug tamoxifen (GI50 = 0.24 μM) against the MDA-MB-231 cell line [79].
In another study, Arshad and coworkers prepared a series of tetrazole-based derivatives and evaluated the biological activity of these compounds against MCF-7 (ER positive), MDA-MB-231 and ZR-75 (ER negative) breast cancer cell lines. The results showed that compounds 81a-c ( Figure 10) exhibited potent inhibitory activity against MCF-7 cells, while compound 81d ( Figure 10) revealed potent activity against both ZR-75 and MDA-MB-231 cell lines [70]. Furthermore, compounds 82a-c unveiled higher potent selectivity toward breast cancer resistance protein (BCRP/ABCG2) than the reference Ko143 ( Figure 10) [80].

Indole-and Oxindole-Based Anti-Breast Cancer Agents
Indole and oxindole moiety, among the widest-spread heterocycles in nature, are used as a building block for many pharmaceutical agents, especially in the discovery of new antitumor agents. [81][82][83][84].  In another study, Arshad and coworkers prepared a series of tetrazole-based derivatives and evaluated the biological activity of these compounds against MCF-7 (ER positive), MDA-MB-231 and ZR-75 (ER negative) breast cancer cell lines. The results showed that compounds 81a-c ( Figure 10) exhibited potent inhibitory activity against MCF-7 cells, while compound 81d ( Figure 10) revealed potent activity against both ZR-75 and MDA-MB-231 cell lines [70]. Furthermore, compounds 82a-c unveiled higher potent selectivity toward breast cancer resistance protein (BCRP/ABCG2) than the reference Ko143 ( Figure 10) [80].
In 2015, Ma et al. synthesized a novel series of indole-benzothiazole derivatives and examined their antitumor activity against four cancer cell lines: HT29, H460, A549 and MDA-MB-231. The assay results showed that compound 90 ( Figure 11) displayed potent cytotoxic activity against MDA-MB-231 with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM, respectively; this was explained by their ability to activate procaspase-3, besides arresting the cell cycle [88]. The reaction of 2-substituted indoles with halogeno-quinone produced indolylquinone derivatives which were designed as potential anti-breast cancer agents. Novel indole derivatives were also designed and synthesized to investigate their biological activity as casein kinase II (CK2) and ABCG2 inhibitors. The results revealed that the compounds having N 5 -isopropyl substituent on the C-ring (88a-c) were the most potent inhibitors of casein kinase II (CK2) (IC 50 = 0.17-0.36 µM) (Figure 11), while compounds containing N 5 -phenethyl substituent on the C-ring (89a-c) displayed significant activity against breast cancer resistance protein ABCG2 (IC 50  respectively; this was explained by their ability to activate procaspase-3, besides arresting the cell cycle [88]. The reaction of 2-substituted indoles with halogeno-quinone produced indolylquinone derivatives which were designed as potential anti-breast cancer agents. The results exhibited that compound 93a displayed significant potency toward MCF-7 (IC 50 = 2.29 µg/mL), while compound 93b was the most active derivative against MDA-MB-231 (IC 50 =3.99 µg/mL) ( Figure 12) [89]. Fluorescence microscopy analysis hinted that indolylquinone derivatives inhibited the growth of BC via triggering apoptotic cell death.
Furthermore, aryl methyl ring substituted analog of 3,3 di Indolyl methane (DIM), Phemindole 94 (Figure 12), was synthesized and evaluated as an anticancer agent toward triple-negative breast cancer (TNBC). This compound exhibited potent activity against MDA-MB-231 cell lines with induction of apoptosis in MDA-MB-231 cells and have antimigration activity by focal adhesion kinase control phosphorylation in the aforementioned cell line [90].
Gamal El-Din et al. developed a series of 1,3,4-oxadiazole derivatives bearing a sulfonamide moiety in order to screen their anticancer activity against a panel of 58 cancer cell lines of nine different types of cancer. Compound 104 ( Figure 14) showed a powerful cytotoxic effect against tested cell lines, especially the T-47D breast cancer cell line with growth inhibition of 90.47% at 10 µM, compared to the reference drugs Paclitaxel and Gefitinib [98]. Additionally, a novel series of coumarin linked to 1,3,4-oxadiazole moiety was synthesized and screened as anti-BC agents against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compound 105 (Figure 14) displayed the most effective potency against MCF-7 cells with an IC 50 value < 5 µM which is about 1.4 times more potent than the reference drug tamoxifen [99].

Oxadiazole-Bearing Small Molecules as Anti-Breast Cancer Agents
A series of novel substituted 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives was prepared and screened for cytotoxicity against BC cells. The target compounds unveiled good activity towards the tested cell lines, in particular, compound 103 (Figure 14), the most potent derivatives with IC50 = 10.25 ± 2.5 and 10.51 ± 1.9 μM against BC MCF-7 and MDA-MB-453 cell lines, respectively. Moreover, the target 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazoles revealed their ability to induce apoptosis [97].  Figure 14) showed a powerful cytotoxic effect against tested cell lines, especially the T-47D breast cancer cell line with growth inhibition of 90.47% at 10 μM, compared to the reference drugs Paclitaxel and Gefitinib [98]. Additionally, a novel series of coumarin linked to 1,3,4-oxadiazole moiety was synthesized and screened as anti-BC agents against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compound 105 (Figure 14) displayed the most effective potency against MCF-7 cells with an IC50 value < 5 μM which is about 1.4 times more potent than the reference drug tamoxifen [99].

Thiazolidine Derivatives
Recently, a new series of thiazolidinone derivatives was synthesized to investigate their bioactivity as anti-breast cancer agents. The results exhibited that compound 106 ( Figure 15) revealed to be the most active compound with IC50 values of 1.9 ± 1.15, 5.4 ± 1.13 and 6.5 ± 1.16 μM against MDA-MB-231, HepG2 and HT-29, respectively. This compound unveiled a promising anticancer agent against TNBC which induces apoptosis via arresting cell cycle at G1/S phase, beside inhibition of angiogenesis [100]. In addition, a new family of 2,3-thiazolidin-4-one derivatives was reported as effective anti-BC agents. Compounds 107a-b (Figure 15) showed potent cytotoxicity towards MCF-7 cells, while compounds 107c-e ( Figure 15) showed remarkable activity against SKBR3 cells [101].

Thiazolidine Derivatives
Recently, a new series of thiazolidinone derivatives was synthesized to investigate their bioactivity as anti-breast cancer agents. The results exhibited that compound 106 ( Figure 15) revealed to be the most active compound with IC 50 values of 1.9 ± 1.15, 5.4 ± 1.13 and 6.5 ± 1.16 µM against MDA-MB-231, HepG2 and HT-29, respectively. This compound unveiled a promising anticancer agent against TNBC which induces apoptosis via arresting cell cycle at G1/S phase, beside inhibition of angiogenesis [100]. In addition, a new family of 2,3-thiazolidin-4-one derivatives was reported as effective anti-BC agents. Compounds 107a-b ( Figure 15) showed potent cytotoxicity towards MCF-7 cells, while compounds 107c-e ( Figure 15) showed remarkable activity against SKBR3 cells [101].   Figure 16) has the ability to repress tubulin polymerization with an IC 50 value of 3.4 µM, beside apoptosis induction, and ultimately cell cycle arrest (G2/M) phase [103]. In addition, the same research group has reported on another series from pyrazole-naphthalene derivatives. Compound 112 ( Figure 16) with IC 50 = 2.78 ± 0.24 µM against MCF-7 cell line, was five times more potent than the reference drug cisplatin (IC 50 = 15.24 ± 1.27 µM). Furthermore, the aforementioned compound 112 ( Figure 16) inhibited tubulin polymerization with IC 50 value of 4.6 µM in addition to induction of apoptosis and cell cycle arrest at the G2/M phase [104]. A novel series of sixteen methyl β-orsellinate-based 3,5-disubstituted isoxazole derivatives was synthesized by Reddy et al. The target compounds were screened in vitro for their anticancer activity against four cancer cell lines: IMR-32, DU-145, MIAPACA and MCF-7. Compound 115 (Figure 16) showed the highest inhibitory potency against the MCF-7 cell line (IC50 = 7.9 ± 0.07 μM) with an induction of apoptosis and cell cycle arrest at the G2/M phase [106].
A series of new pyrazole derivatives has been synthesized and screened in vitro as anti-BC targeting VEGFR-2 kinase. The assay results displayed that compounds 116a-e and 117 (Figure 16) exhibited the most potent activity against MCF-7 cell line with the value of IC50 ranging (16.50-26.73 μM) compared to tamoxifen (IC50 = 23.31 μM). Furthermore, the synthesized compounds, especially 116b-e and 117, showed significant inhibitory activities toward VEGFR-2 kinase with inhibition activity (70-79%). In particular, compounds 116c, 116e and 117 unveiled the most inhibitory efficiency with IC50 in nanomolar range (913.51, 225.17, and 828.23 nM, respectively) in comparison to the reference drug sorafenib (IC50 = 186.54 nM) [107].  Figure 16) exhibited the higher cytotoxicity to oestrogen-responsive human breast cancer MCF-7 compared to the standard drug tamoxifen. Moreover, compound 114 ( Figure 16) showed significant binding and antagonistic effects against human ER in an in vitro assay [105].
A series of new pyrazole derivatives has been synthesized and screened in vitro as anti-BC targeting VEGFR-2 kinase. The assay results displayed that compounds 116a-e and 117 ( Figure 16) exhibited the most potent activity against MCF-7 cell line with the value of IC 50 ranging (16.50-26.73 µM) compared to tamoxifen (IC 50 = 23.31 µM). Furthermore, the synthesized compounds, especially 116b-e and 117, showed significant inhibitory activities toward VEGFR-2 kinase with inhibition activity (70-79%). In particular, compounds 116c, 116e and 117 unveiled the most inhibitory efficiency with IC 50 in nanomolar range (913.51, 225.17, and 828.23 nM, respectively) in comparison to the reference drug sorafenib (IC 50 = 186.54 nM) [107].

Benzofuran Derivatives
Benzofuran-based small molecules are well known in medicinal chemistry for their diverse, broad spectrum anticancer activity. Coskun et al. designed and synthesized a new series of benzofuran substituted chalcone derivatives and studied their in vitro antitumor activities by MTT assay. The results indicated that the tested compounds revealed cytotoxic activity against malignant MCF-7 and PC-3 cell lines, in particular compound 118 (Figure 17) with the value of log IC 50 = 0.42 and 0.67 µM, respectively [108]. One year later, in 2021, novel sets of ureido benzofurans incorporating sulfonamide functionality (123, Figure 17) were developed as anti-breast cancer agents targeting cancer-related hCA IX and XII isoforms. Several derivatives potently inhibited the cancerrelated hCA IX isoform within the single-digit nanomolar range (KIs: 1.8 -8.4 nM). Further MTT assay was performed, which ascribed potent anti-proliferative impact to 124a against BC MCF-7 cells (IC50 = 6.  Figure 17) [111].
Additionally in 2021, the design and synthesis of novel sets of 5-bromobenzofuranbased small molecules tethered with indolin-2-one (125, Figure 17) moiety were described by Eldehna et al. [112]. The target benzofuran-indolinone conjugates were developed as dual inhibitors for the two key oncotargets CDK2/GSK-3β that are involved in breast cancer. All the reported benzofuran-indolinone conjugates in this study were screened for their anti-breast cancer activity towards T-47D and MCF-7 cell lines. Superiorly, conjugates incorporating N 1 -unsubstituted indolinone moieties exerted moderate to It is also reported that a novel series of benzofuran derivatives was designed and synthesized as potential oestrogen receptor inhibitors endowed with anti-breast cancer activity. Among these compounds, 2-benzoyl-3-methyl-6-[2-(morpholin-4-yl)ethoxy] benzofuran (119) (Figure 17) owned the most potent activity against MCF-7 human breast cancer cells with inhibitory percentage of 64.23% at 50 µM and showed a low toxicity toward normal cells. Moreover, a comprehensive structure-activity relationship was extracted from this study [109].
In 2020, Eldehna et al. reported the design and synthesis for new 2-methylbenzofuran 120 or 5-bromobenzofuran 121 derivatives featuring the carboxylic acid functionality represented in the benzoic and hippuric acid moieties ( Figure 17). The target 2-methylbenzofuran or 5-bromobenzofuran derivatives were assessed for their inhibitory action against cancerrelated human carbonic anhydrases (hCA) IX and XII isoforms. They displayed good inhibitory activity and selectivity toward hCA IX isoform (K I s ranging from 0.56 to 5.1 µM), and subsequently the most potent inhibitors were screened for their potential antitumor impact against two human breast cancer cell lines, MCF-7 and MDA-MB-231. In particular, 5-bromobenzofuran-based counterpart 122 exerted the best anti-proliferative action against the examined TNBC MDA-MB-231 cells (IC 50 = 2.52 ± 0.39 µM) which was comparable to doxorubicin (IC 50 = 2.36 ± 0.18 µM). Moreover, compound 122 significantly elevated (from 0.78 to 31.88%) the Annexin V-FITC positive MDA-MB-231 apoptotic cells, as well as led to a cell cycle disturbance through alteration of Sub-G 1 phase and arrest of G 2 -M stage ( Figure 17) [110].
One year later, in 2021, novel sets of ureido benzofurans incorporating sulfonamide functionality (123, Figure 17) were developed as anti-breast cancer agents targeting cancerrelated hCA IX and XII isoforms. Several derivatives potently inhibited the cancer-related hCA IX isoform within the single-digit nanomolar range (K I s: 1.8-8.4 nM). Further MTT assay was performed, which ascribed potent anti-proliferative impact to 124a against BC MCF-7 cells (IC 50 Figure 17) [111].

Miscellaneous Anti-Breast Cancer Agents
A new series of thirty-three combretastatin A-4 (CA-4) analogs conjugated to piperazine moiety was synthesized via Perkin reaction by Boyle et al. in 2019 [113] and tested against MCF-7 breast cancer cells. Compounds 127a-c ( Figure 18) showed potent antiproliferative activity against MCF-7 cells with a range of IC 50 : 83-190 nM, as well as induced apoptosis via arresting cell cycle G2/M phase in MCF-7 cancer cell line. Moreover, the developed CA-4 analogs were able to act directly on tubulin as microtubule-destabilizing agents. Moreover, another research group developed a novel series of cyclohexyl thiosemicarbazone derivatives to screen their cytotoxic activity. Compound 128 (Figure 18) displayed the highest activity against three breast cancer cell lines: MDA-MB-468, MDA-MB-231 and SKBr-3, with a range of IC 50 values of 24.50 ± 0.01-32.2 ± 0.09 µM. Unfortunately, the aforementioned compounds did not show any activity against breast cancer MCF-7 cell lines [114].
In 2014, Weldon et al. synthesized a series of cinnamylidene acetophenones and studied their anticancer activity. The results indicated that compounds 129a-b ( Figure 18) displayed sub-micromolar activity toward MDA-MB-468 and MCF-7 cells with relatively less activity against normal cell MCF-10A cells [115]. In addition, Varela and coworkers synthesized three metabolites of the steroidal aromatase inhibitor exemestane and tested them against MCF-7aro cells. Steroid 130 (Figure 18) displayed the most potent inhibition of MCF-7aro cells viability with IC 50 of 0.25 µM. In addition, it induces loss of plasma membrane integrity [116].
the developed CA-4 analogs were able to act directly on tubulin as microtubuledestabilizing agents. Moreover, another research group developed a novel series of cyclohexyl thiosemicarbazone derivatives to screen their cytotoxic activity. Compound 128 (Figure 18) displayed the highest activity against three breast cancer cell lines: MDA-MB-468, MDA-MB-231 and SKBr-3, with a range of IC50 values of 24.50 ± 0.01-32.2 ± 0.09 μM. Unfortunately, the aforementioned compounds did not show any activity against breast cancer MCF-7 cell lines [114].  Figure 19) were found to be more effective than the reference (ospemifene and tamoxifen) against MDA-MB-231 cells (IC 50 = 25 and 17.1 µM, respectively) and against MCF-7 cells (IC 50 = 15.9 and 23.6 µM, respectively). Moreover, compound 137 ( Figure 19) showed potent cytotoxic activity against MCF-7 cells (IC 50 = 76 µM) comparable to that of ospemifene and tamoxifen [119]. Furthermore, Kaur et al. developed a novel series of ospemifene analogs and tested their cytotoxic activity against MDA-MB-231 (ER-negative) and MCF-7 (ER-positive) cancer cell lines. The novel compounds 134 and 136 ( Figure 19) were found to be more effective than the reference (ospemifene and tamoxifen) against MDA-MB-231 cells (IC50 = 25 and 17.1 μM, respectively) and against MCF-7 cells (IC50 = 15.9 and 23.6 μM, respectively). Moreover, compound 137 ( Figure 19) showed potent cytotoxic activity against MCF-7 cells (IC50 = 76 μM) comparable to that of ospemifene and tamoxifen [119].  [120]. The second study reported the conjugation of the thiazolo[3,2-a]benzimidazole framework with a benzenesulfonamide moiety through urea (139, Figure 19) or enaminone (140, Figure 19) linkers to furnish a novel class of potent and selective inhibitors of cancerrelated hCA IX and XII isoforms with inhibition constants in the nanomolar range. The most potent CA inhibitors displayed further efficient cell growth inhibitory activity  [120]. The second study reported the conjugation of the thiazolo[3,2-a]benzimidazole framework with a benzenesulfonamide moiety through urea (139, Figure 19) or enaminone (140, Figure 19) linkers to furnish a novel class of potent and selective inhibitors of cancer-related hCA IX and XII isoforms with inhibition constants in the nanomolar range. The most potent CA inhibitors displayed further efficient cell growth inhibitory activity against BC MCF-7 and MDA-MB-231 cell lines under both normoxic and hypoxic conditions. Further investigations revealed their impact on induction of apoptosis and cell cycle progression [121].
On assessed their in vitro anti-proliferative activity. The results showed that most of the synthesized compounds displayed good activity, in particular compounds 141 and 142 ( Figure 20) exerted the best activity against MCF-7 (IC50 = 56 and 47 μM, respectively) and MDA-MB-231 (IC50 = 61 and 87 μM, respectively) cell lines [122].
Interestingly, organometallic complexes have taken reputation as effective and potent anticancer agents. Accordingly, three nano Ni(II) and Cu(II) complexes 148-150 ( Figure 21) were synthesized via condensation reaction of 2-hydroxy-3- Interestingly, organometallic complexes have taken reputation as effective and potent anticancer agents. Accordingly, three nano Ni(II) and Cu(II) complexes 148-150 ( Figure 21) were synthesized via condensation reaction of 2-hydroxy-3-methoxybenzaldehyde with ethylamine or N,N-dimethyl-1,2-diaminoethane, followed by a complexation of the obtained Schiff base with Cu(NO 3 ) 2 .3H 2 O and Ni(NO 3 ) 2 .6H 2 O. The new complexes' particle diameters were decreased using green manual grinding technology and the antiproliferative activity of the produced complexes was assessed against the MCF-7 cancer cell line. The results displayed that complex 148 ( Figure 21) revealed significant anticancer activity against MCF-7 cancer by inducing apoptosis [127].
In addition, it was reported that three novel platinum(IV) complexes were synthesized and screened for their anticancer activity. Compound 151 (Figure 21) showed the highest cytotoxic activity against MDA-MB-231 (IC 50 = 68.023 µM) with induction of apoptosis [128].
Furthermore, two complexes of platinum(II) dichloride were synthesized and investigated against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compounds 152 and 153 ( Figure 21) showed potent inhibition activity and induced apoptosis in a similar way to cisplatin on tested cells. They also revealed anti-migration activity of MDA-MB-231 cells by decreasing the levels of metabolic energy (ATP), distressing cytoskeletal organization membrane and cell polarity [129].
Furthermore, two complexes of platinum(II) dichloride were synthesized and investigated against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compounds 152 and 153 ( Figure 21) showed potent inhibition activity and induced apoptosis in a similar way to cisplatin on tested cells. They also revealed anti-migration activity of MDA-MB-231 cells by decreasing the levels of metabolic energy (ATP), distressing cytoskeletal organization membrane and cell polarity [129].

Conclusions and Future Perspective
Heading the list of critical health-associated problems worldwide, breast cancer stands as one of the most serious diseases responsible for a huge number of cancer-related mortality among women. Accordingly, development of novel efficient agents for management of the human breast malignancies is an urgent necessity. In this regard, Figure 21. Organometallic complexes as anti-breast cancer agents.

Conclusions and Future Perspective
Heading the list of critical health-associated problems worldwide, breast cancer stands as one of the most serious diseases responsible for a huge number of cancer-related mortality among women. Accordingly, development of novel efficient agents for management of the human breast malignancies is an urgent necessity. In this regard, considerable progress in the field of drug design and medicinal chemistry has been achieved, and several synthetic small molecules based on diversified chemical scaffolds have been identified as promising anti-breast cancer agents. This review summarized the recently reported different categories exploited to develop the synthetic anti-breast cancer candidates. To name just a few: quinoline, quinazoline, pyridine, pyridazine, pyrimidines, imidazole, benzimidazole, coumarin, tetrazole, indole, oxindole and triazine scaffolds were discussed in this review article. Moreover, the significant structure activity relationships, bioactivities and mechanistic insights for the reported small molecules were further concluded. It is worth stressing that surveying literature disclosed that there is a shortage in addressing invasion, migration and metastasis of BC, which reflects a discrepancy between the need and the assays for most of the reported anticancer agents. The present review article is expected to be contributory for the drug discovery community to support the future design and development of more potent, safer and selective candidates for breast cancer therapy.

Conflicts of Interest:
The authors declare no conflict of interest.