Flavone Hybrids and Derivatives as Bioactive Agents

Abstract

Hybrid molecules can be defined as chemical entities with two or more structural domains, namely pharmacophores, having a specific biological effect. In many cases, when at least one of the components is biologically inactive, it is rather correct to call them “derivatives”, despite the fact that in the literature they are often mentioned also as hybrids. We have summarized such types of molecules, in which one of the components is mostly a real pharmacophore, i.e., flavone, which is one of the best-known natural bioactive substances. Structures, synthetic methods, medicinal indications, and more important activity data are presented.

1. Introduction

Flavones are among the widely known and biologically recognized natural compounds. Their characteristic basic structure is the phenylbenzopyrone skeleton. Depending on their structure, flavones have a different range of biological effects, such as antioxidant, antimicrobial, anticancer, antimalarial, anti-inflammatory, antiulcer, and anti-HIV effects [1,2].

Perhaps the best known of them are chrysin (1), kaempferol (2), and quercetin (3), which differ in the number and position of the hydroxyl groups (Figure 1). Chrysin (1) occurs in larger quantities in many plant species and in honey. It causes inhibition of cell proliferation through apoptosis and autophagy [3]. Kaempferol (2) and its derivatives are also found in plants, e.g., in beans, broccoli, strawberries, and tea fruits. Diets rich in fruits and vegetables can reduce the risk of coronary heart disease and cancer [4]. Quercetin (3) is found in onions, among many other plants. It causes the cancer-preventive effect through its antioxidant properties, by inhibition of various enzymes, and with modulation of signaling pathways [5].

Compounds containing two pharmacophores coupled covalently, i.e., hybrids, are described in most detail by Nepali et al. [6]. The types of hybrid molecules cover generally three possibilities (Figure 2). The two pharmacophores can be connected by a link-er chain (a), rigid or mobile, and can only be regularly substituted with one covalent bond, (b) or the two molecules can be simply merged (c) [7,8].

Hybrid molecules can also be classified according to the origin of the monomers. We distinguish between natural, synthetic, and mixed hybrids. The first two types consist of purely natural or synthetic units, while the third contains both.

There are several reviews in the literature about flavone hybrids, which primarily present a specific field of biological activity, e.g., anticancer agents [9] or esterase inhibitors [10]. On the other hand, further reviews summarize flavone hybrids formed with specific coupling components, such as 2-pyrrolidones (flavone alkaloids) and arylamines [11], with Vinca alkaloids [12] as well as 1,2,3-triazole pharmacophores [13].

Hundreds of molecules are known in the literature, in which the main component is flavone. Considering the nomenclature problems between “hybrids” and “derivatives”, we chose the solution of summarizing those compounds that were named hybrids by the cited authors themselves. Thus, in this review, flavone hybrids containing different pharmacophores are presented highlighting their biological effects.

As far as synthetic routes, flavones, like many other pharmacophores, e.g., amino acids (Section 2.3), carotenoids, and Vinca alkaloids (Section 2.4), are also natural substances, but the hybrids under discussion themselves are prepared synthetically. There are only a few hybrids of natural origin; these are mentioned in Section 2.7.

Classification of hybrids presented regarding the extraordinary diversity of the structure of the pharmacophores is presented from the point of view of importance and significance.

2. Flavone Hybrids with Different Pharmacophores

As can be seen, a lot of hybrids were synthesized, among which are the most important ones that were further investigated in different fields. These are considered the most typical structures, and examples of these characteristic hybrids are presented in

Table 1. The most characteristic hybrid skeletons of flavones and their biological activities.

Flavone	Pharmacophore	Biological Effect	Activity *	Control Activity	Section	Reference
chrysin	1,2,3-triazoles	antibacterial	MIC = 6.25 µg/mL (E. coli)	penicillin, MIC = 50 µg/mL	2.1.	[14]
chrysin	1,2,3-triazoles	antiproliferative	IC50 = 0.733 µM (HeLa)	cisplatin, IC50 = 12.2 µM	2.1.	[15,16]
6-aminoflavone	1,2,3-triazoles	antiproliferative	GI50 < 0.01 µM (MDA-MB-231)	paclitaxel, GI50 = 0.091 µM	2.1.	[17]
luteolin	1,2,3-triazoles	antiplasmodial	IC50 = 3.85 µM (P. falciparum 3D7)	artemisinin, IC50 = 1.12 µM	2.1.	[18]
quercetin	triphenylphosphine	antioxidant	EC50 = 6.3 µM (DPPH assay)	quercetin, EC50 = 6.0 µM	2.2.	[19,20]
chrysin	amino acids	antiproliferative	IC50 = 3.78 µM (MGC-803)	cisplatin, IC50 = 4.40 µM	2.3.	[21,22]
quercetin	amino acids	MDR modulator	IC50 = 0.14 µM (MES-SA/Dx5)	doxorubicin, IC50 = 8.20 µM	2.3.	[23]
2-phenylchromen- 4-one	amino acids	antiproliferative	IC50 = 9.2 µM (CCRF-CEM)	n.d.	2.3.	[24]
chrysin	vindoline	antiproliferative	GI50 = 1.1 µM (LOX IMVI)	n.d.	2.4.	[12]
chrysin	morpholine	antibacterial	MIC = 6.25 µg/mL (B. sphaericus)	streptomycin, MIC = 12.5 µg/mL	2.5.	[25]
chrysin	piperazines	antitumor	IC50 = 4.67 µM (HeLa)	gefitinib, IC50 = 17.9 µM	2.5.	[26]
apigenin	piperazines	antitumor	IC50 = 0.0147 µM (PARP-1 inhibition)	olaparib, IC50 = 0.0051 µM	2.5.	[27]
2-phenylchromen- 4-one	imidazo[1,2-a] pyridine	antiplasmodial	IC50 = 1.98 µM (P. falciparum K1)	chloroquine, IC50 = 0.25 µM	2.6.	[28]
2-phenylchromen- 4-one	2-amino-thiazole	antibacterial	MIC = 12.5 µg/mL (B. lintus)	ciprofloxacin, MIC < 1.5 µg/mL	2.6.	[29]
7-hydroxyflavone	dihydro-1H-furo[2,3-c]pyrazole	antitumor	IC50 = 2.5 µM (Hep2)	doxorubicin, IC50 = 10 µM	2.6.	[30]
7-hydroxyflavone	acridine	monoamine oxidase inhibitor	IC50 = 3.24 µM (MAO-B inhibition)	tacrine, IC50 = 7.85 µM	2.6.	[31]
5,6,7-trimethoxy- flavone	6-chlorotacrine	anti-Alzheimer’s disease	IC50 = 0.0128 µM (AChE inhibition)	6-chlorotacrine, IC50 = 0.0785 µM	2.6.	[32]
chrysin	apigenin	antiproliferative	IC50 = 0.179 µM (PARP-1 inhibition)	olaparib, IC50 = 0.0051 µM	2.7.	[27]
mosloflavone	resveratrol	anti-inflammatory	IC50 = 0.31 µM (PGE2 inhibition)	n.d.	2.8.	[33]
2-phenylchromen- 4-one	naphthopyran	xanthine oxidase inhibitor	IC50 = 0.62 µM (XO inhibition)	apigenin, IC50 = 1.11 µM	2.9.	[34]
2-phenylchromen- 4-one	estradiol	antiproliferative	IC50 = 3.9 µM (HeLa)	cisplatin, IC50 > 330 µM	2.9.	[35]
kaempferol	carbohydrate	antibacterial	MIC = 0.05 µg/mL (S. gallinarum)	ciprofloxacin, MIC = 0.25 µg/mL	2.9.	[36]

* The activities presented are the value of the most effective derivative. The type of microorganism or cell line tested is shown in parentheses.

together with their biological activities.

2.1. Hybrids with 1,2,3-Triazoles and Their Derivatives

1,2,3-Triazole, as a well-known pharmacophore, and its derivatives have many positive properties, e.g., moderate dipole character, rigidity, stability shown in in vivo conditions, ability to form hydrogen bonds—which increases water solubility, as well as the possibility of binding to various biomolecules—led to the fact that its use in hybrids is very important. The ring itself does not occur in nature, although its compounds are known to have many bioactivities, such as anticancer, fungicidal, antibacterial, anti-HIV, antituberculosis, and antimalarial effects. The importance of the compounds containing the 1,2,3-triazole unit in medicinal chemistry is unquestionable, since—in contrast to other heterocycles—it is not protonated at a physiological pH due to its weak basicity [37,38].

One of the most classic flavone hybrid groups comprises compounds coupled with substituted 1,2,3-triazoles (Figure 3).

Thus, chrysin was reacted with propargyl bromide, and the propargyl derivative was subjected to a click reaction with various benzyl azide derivatives (prepared in situ) [14], resulting in the chrysin hybrids coupled with the pharmacophore in position 7. The antibacterial activity of the new compounds was investigated on 3-3 Gram-positive and Gram-negative pathogenic bacteria strains, respectively. Most of the derivatives showed moderate-to-excellent antibacterial effects.

Then, it was pointed out [15] that compound 5 (R=F, NO₂) and its dimer derivative (6) (Figure 4) have moderate antiproliferative activity on several cell lines of different types of cancer. Among these, compound 6 (R=F) is the most important, with an IC₅₀ = 0.73 µM activity on HeLa cells.

Chrysin triazole hybrids substituted on the triazole ring with an aryl group (7) (Figure 4) were synthesized with the general procedure, including the click reaction of the propargyl intermediate [16]. The compounds were investigated on several cancer cell lines and the best result was IC₅₀ = 5.9 µM on the human gastric carcinoma cell line MGC-803. Replacing the 1,2,3-triazole ring to 1,2,4-triazole yielded no significant biological effect.

Antiproliferative and antimycobacterial flavone hybrids were synthesized containing two heterocyclic pharmacophores, isoxazole and benzimidazole [39]. The synthetic routes are presented in Figure 5. The merged isoxazole hybrid (9) was formed by the cyclization of the corresponding oxime prepared by the 4-formyl derivative (8), and the benzimidazole substituent (10) was built in with the usual procedure via reaction with o-phenylendiamine. Hybrid 11 was obtained in this case also via a click reaction.

Some of the compounds (11) showed moderate antiproliferative activity on cell line MCF-7 of breast cancer (IC₅₀ = 14.5–19.1 µM), and hybrid 9 (R=CH₃, R¹=H) showed moderate antimycobacterial activity against a bovis strain.

The triazole ring is connected to the flavone via an amino group in the following hybrids (Figure 6). Amino derivative 12 was prepared via cyclization of the corresponding acylamino derivative and was then deacetylated. After an alkylating reaction with propargyl bromide, the resulting N-propargyl intermediate 13 was treated with azides and after the usual click reaction, the 14 hybrids were obtained [17]. The antiproliferative activity was tested on different human cancer cells, such as cervical, pancreatic breast, and neuroblastoma. The most promising result was against the MDA-MB-231 breast cancer cell line with GI₅₀ ≤ 0.01 µM of compound 14 (R=4-nitrobenzyl).

The triazole ring was not only formed on the aromatic A ring of flavones, but also on the phenyl group (C ring) in position 2 (Figure 7).

Apigenin-7-methyl ether derivatives (15) were prepared employing a known procedure via a click reaction of the propargyl intermediate [40]. This type of compound especially 15 (R=2-F-phenyl) showed potent antitumor activity (IC₅₀ = 10 µM) against ovarian carcinoma cell line SKOV-3. A high number of compounds 16 have been investigated, also using in silico methods [41]. Upon experimental tests, primarily the R=halogen-substituted compounds proved to have antibacterial and antifungal effects [18].

Finally, two more examples are presented (Figure 8). One of them belongs to the group of biologically exciting nucleoside analogs [42]. In these compounds, the triazole is linked to chrysin and the deoxythymine derivative together (17). The target compound was synthesized as of these types of hybrids, namely, a 1,3-dipolar cycloaddition reaction between the O-propargyl derivative of chrysin and 3′-azido-2′-deoxythymidine.

The second example is polyfluorinated flavones substituted on the phenyl ring by one or more 1,2,4-triazole rings (18). The rate of substitution depends on the reaction conditions and the excess of triazole. Weak fungistatic activity was observed among the prepared derivatives [43].

2.2. Hybrids with Triphenylphosphine

One of the ways to attack cancer cells is to introduce the drug into the mitochondria. For this, four main strategies were developed: the use of lipophilic cations, the use of cell-penetrating peptides, the application of nanoparticles, and physical penetration. Among them, the most commonly used method is the use of lipophilic cations [44].

Triphenylphosphonium (TPP⁺)-based cations have a hydrophobic surface and can easily diffuse through the inner membrane. In addition, it was shown that TPP⁺ cations can localize in the mitochondrial matrix, at a concentration 1000 times higher than in the cytoplasm [45]. Since cancer cells have an increased mitochondrial and plasma membrane potential compared to healthy cells, the TPP⁺ cation can cause selective cell death [46].

As proof of this, quercetin and triphenylphosphine hybrids were synthesized using a 4C linker chain (Figure 9). During the course of the synthesis, the specific substituted flavone (19) with protecting groups was treated with the corresponding dihalogen butane, followed by a deacetylation reaction, producing the molecule coupled with the linker (20). After an activation step with NaI, a reaction with triphenylphosphine afforded the mitochondria-targeted derivative 21 [19].

The correlation between oxidative behavior and cytotoxic effect was established by examining Jurkat cells [20].

Further derivatives were synthesized (Figure 10) and also presented their mitochondrial accumulation.

The side chain containing the triphenylphosphonium salt was also built in two different places of the polyphenol, in positions 3 and 5, respectively [47].

Moreover, compound 21 was conjugated with mitochondria-targeted self-assembled nanoparticles, and in vitro cytotoxicity to HeLa, HepG2, MCF-7, and A549 cells were investigated and showed that the nanoparticles were more effective therapeutic agents compared to quercetin [48].

2.3. Flavone Hybrids with Amino Acids

Most often, the amino acid side chain was formed in position 7 of flavones, and chrysin proved to be the most used flavone among them. Thus, several amino acids were coupled to chrysin for metabolic studies, e.g., glycine, alanine, valine, leucine, methionine, etc. [49].

Two methods were used known from peptide chemistry. In the first one, after hydrolysis of 24, hybrids were obtained. In compound 26, the amino acid was coupled to the flavone via a short linker (Figure 11).

The hybrids of 27 (Figure 12) were prepared employing similar procedures; however, at the coupling reaction with amino acids, the well-known N-hydroxybenzotriazole–EDCI system was used [21].

The most potent antiproliferative activity was obtained in the case of compound 27 (R=butane-2-yl, R¹=Me, n = 1; isoleucine ester hybrid; IC₅₀ = 3.78 µM against human gastric carcinoma MGC-803 cell lines).

Compounds with a similar structure were also prepared with a longer linker (Figure 12). Amongst these, 27 (R=2-Me-propyl, R¹=H, n = 4; leucine hybrid) proved to be an effective anticancer molecule. On the breast cancer MCF-7 cell line, IC₅₀ = 16.6 µM was obtained; moreover, the compound displayed moderate inhibition of EGFR [22].

Further derivatives of flavones combined with amino acids are compounds where the short linker is substituted with a long carbon chain alkyl group (Figure 12). Compound 28, where the amino acid component is leucine in methyl ester form (R¹=Me) showed good activities on breast cancer cells MCF-7 cell line (IC₅₀ = 32.7 µM) and on MDA-MB-231 (IC₅₀ = 8.2 µM) [50]. In addition, compound 28 had outstanding selectivity between other cancer cells and human vascular endothelial cells.

Amino acids containing apigenin (29) and quercetin derivatives (30) were also synthesized using protected amino acids. From the apigenin hybrids, the Lys-coupled molecule proved to be the best on the biological tests, having a sedative effect on mouse brain tissues (single dose 0.4 mg/g) passing through the blood–brain barrier [51]. In the case of the quercetin–glutamic acid conjugate (IC₅₀ = 0.14 µM on drug-resistant human MES-SA uterine sarcoma cell line), a potent Pgp-based MDR-modulating effect was found [23].

Flavone–amino acid hybrids (32) were prepared from 7-bromo derivative (31) employing the Buchwald–Hartwig reaction conditions (Figure 13). Not only were single amino acid-containing derivatives (32a) synthesized, but also dipeptide hybrids (32b).

The products were investigated on several cancer types [24], and hybrids coupled with single-amino acid esters hydrolyzed to the corresponding carboxylic acids proved to be the most effective, especially 32a (A=Val, R=H). However, it should be noted that the authors did not use a positive control in the course of the screening, which is a non-recommended practice.

2.4. Flavones Coupled with Representative Natural Components

Flavones containing a carotenoid-like side chain were synthesized from the corresponding C₂₆-aldehyde and the phosphorous ester-substituted flavone using the Wittig–Horner–Emmons reaction (Figure 14). Antioxidant characteristics of products 33 (R=H, OH) were investigated [52].

Furthermore, the UVA photoprotective properties of compound 33 (R=OH) were also tested [53].

Important groups of natural compounds are the flavone alkaloids and Vinca alkaloids [11]. Flavone hybrids of vindoline (Figure 14) coupled in position 10 of vindoline (34, 35) were synthesized with short or longer linkers. The connection of vindoline was also built to position 17 using a 4C linker (36) via known procedures. From the new derivatives, compound 34 showed important antiproliferative activity in several cell types, and an excellent GI₅₀ value (1.1 µM) was obtained on the melanoma LOX IMVI cell line [12].

2.5. Cyclic Saturated Amines in Flavone Derivatives

Chrysin analogs (37) with antibacterial activities were synthesized using the maximum number of 6C long spacers (Figure 15).

Morpholine, piperidine, and N-methylpiperazine were the coupling components and the key intermediate bromoalkyl chain was prepared from chrysin with dibromoalkanes [25]. The sulfonylpiperazine hybrids (37d) proved to be antioxidant and cytotoxic agents [26]. The halogen analogs (37d, R¹=Cl, diCl, diF) showed anticancer effects against the SK-OVS (human ovarian cancer), HeLa (human cervical cancer), and HT-29 (human colon adenocarcinoma) cell lines; the methoxy and dimethoxy derivatives proved to be effective against the A-549 (human non-small cell lung carcinoma) and HT-29 cell lines (minimum value of IC₅₀ = 4.67 µg/mL). At the same time, it should be mentioned that no positive control was used in the cytotoxicity assays, only literature data for gefitinib were obtained.

Several flavone hybrids substituted in position 8 with piperazine (38) and piperidine (39) were prepared (Figure 16). The key step in the synthesis was a typical Mannich reaction between flavone 40 and the piperazine derivative in the presence of paraformaldehyde, resulting in the desired product 38. Compound 38 (R=thiophen-2-ylmethyl) showed an excellent IC₅₀ for PARP-1 (14.7 nM) and in PARP-2 (0.9 µM) inhibition; thus, this hybrid could be considered a lead molecule in cancer treatment [27]. Moreover, the above-mentioned compound exerted a selective cytotoxic effect on breast cancer gene 1 (BRCA1)-deficient cells (SK-OV-3 cells) via inhibiting PARP-1. Poly(ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of anticancer drugs.

The nipecotic acid–flavone hybrids (39) were characterized as anti-Alzheimer agents [54] with a similar synthetic route.

2.6. Heterocyclic Pharmacophores

Flavone hybrids were synthesized with several different heterocycles (Figure 17). In connection with this type of hybrid, only a single paper was published; there was no more special continuation of research on the corresponding structures. Thus, they are briefly presented, highlighting the most effective derivative.

Maleinimide derivatives (41), similar to some flavone alkaloids, can be classified here with antiinflammatory activity [55]. Some imidazopyrimidine hybrids (42) showed antiplasmodial activity [28].

Compound 43 containing a thiazole ring displayed antifungal activity against C. albicans with an MIC of 12.5 µg/mL [29]. Furopyrazol-substituted hybrids (44) with an antiproliferative effect were prepared in large quantities with different substituents in the aromatic ring and in the 2-phenyl group. On cell lines HEP-2 (human laryngeal carcinoma), A549 (human lung adenocarcinoma), and HeLa, IC₅₀ = 2.5–10.0 µM values were obtained [30]. Furthermore, toxicity studies revealed that compound 44 specifically targets cancer cell lines.

1,3-Oxazines coupled in two different positions to the flavone skeleton (45a,b) exhibited excellent activities against both hormone-dependent and hormone-independent human breast cancer cells and against HeLa cells (IC₅₀ = 14–18 µM) [56].

Flavone–triazine hybrids (46) possessed good anticancer activity on human breast cancer cells (MCF-7) [57], and acridine derivatives (47, 48) coupled via shorter and longer linkers [31,32] proved to be MAO inhibitors and anti-Alzheimer agents, respectively. From a pharmacological point of view, the hybrid containing a benzodiazepine ring (49) is a very exciting structure combination. In the case of n = 3, the compound showed significant DNA binding activity, as well as in vitro cytotoxicity [58].

2.7. Flavone–Flavone and Flavone–Coumarin Hybrids

Different analogs of amentoflavone (50, R=OH, R¹=4-OH, AMF) were synthesized (Figure 18) via a convergent total synthetic route [27].

The new compounds, especially 50 (R=H, R¹=4-F), proved to be PARP-1 and PARP-2 inhibitors, with IC₅₀ = 179.2 nM and 8.5 µM activities, respectively. Nevertheless, AMF (a natural compound), isolated from Selaginella moellendorffii Hieron, has a selective PARP-1-inhibitory effect. A further natural compound is the 51 flavone–coumarin hybrid, which was isolated from a Yemenien plant Gnidia socotrana. The connection formed between positions 8 and 6″; moreover, another hybrid was also isolated with 6–8″ coupling, which is regarded as an atropisomer [59]. Several derivatives of this isolated hybrid (51) were synthesized; thus, the anti-diabetic compounds 52 were prepared via Suzuki coupling in the key step [60].

Among the flavone–coumarin hybrids, the substituted compounds 53 had a common aromatic A ring (AA′). According to this, they are merged hybrids [61]. These derivatives were synthesized from the flavone ring provided with the corresponding reactive substituents.

2.8. Aryl Derivatives of Flavones

The aryl-substituted flavones are summarized in Figure 19. Compound 54 was prepared via Suzuki cross-coupling between the corresponding 3-bromoflavone and 3,4,5-trimethoxybenzeneboronic acid under usual reaction conditions and using the required protecting groups. Derivative 55 was obtained via Knoevenagel condensation of the 2,3-dihydroflavone (i.e., the appropriate flavanone) with 3,4,5-trimethoxybenzaldehyde in the presence of a piperidine base. Compounds 54 and 55, together with some similar derivatives, presented moderate tubulin polymerization-inhibitory activity [62].

Aryl derivatives coupled with the 2-phenyl group via an amide bond (56) were synthesized using linear synthetic methods. The amide group was formed by the reactions of the corresponding carboxylic acids and amines [63,64,65]. Compounds 56a,b,c,d showed potent anticancer activity in several cancer cells, and proved to be potential lead molecules for further investigations [66]. It is important to emphasize that compound 56b,d exhibited IC₅₀ values above 100 µM in two non-tumor cell lines (L132 (human lung epithelial cell) and IOSE-80PC (human ovarian epithelial cell)) using MTT cells viability assay. This suggests that these derivatives are selective for cancer cells.

Further effects were also obtained for 56e,f,g (where g is the same as d), showing a promising possibility for the development of anti-inflammatory agents on the base of biological investigations of proinflammatory mediators [33]. However, it should be noted that no positive control was used during the determination of the IC₅₀ values in connection with PGE₂ production inhibition.

In the course of changing the methoxy substituents to methyl or halogen, especially chloro atom, the hit compounds obtained (56h,i) proved to have a potential inhibitory effect against the STE20/GCK-IV kinase family [63].

Molecule 57 was selected from the many similar compounds [64] as the most potent derivative.

Arylamino flavone 55 exhibited nanomolar antiproliferative activity in the MCF7 cell line (breast cancer, GI₅₀ = 30 nM) and the HCT-15 cell line (colon cancer, GI₅₀ = 60 nM).

2.9. Miscellaneous

Recently, a review was published presenting only very few hybrids, focusing more on flavone derivatives and especially the detailed synthetic procedures together with biological activities [65].

Finally, without any detail, some flavone hybrids are presented that cannot be classified into any of the above groups and for which no further investigation data were found. Although in some cases, their biological effects are important, these compounds did not form a large family of further derivatives.

The following figure (Figure 20) shows some typical hybrid skeletons which are also worth mentioning among the miscellaneous structures.

Flavones with a thiosemicarbazone side chain showed antimicrobial activity [67]. In addition, flavones bearing a hydroxamic acid across an alkyl chain linker showed anti-tumor activity against breast cancer [68]. Stilbene coupled to flavones in position 7 (58) exhibits potential antimalarial effects (IC₅₀ = 5.07 μM) [69]. Flavone–cyanoacetamide adducts [70] possess strong AChE-binding affinity, allowing for the possibility of innovative drug development for AD. Flavones, thioflavones, and selenoflavones containing a naphthyl group in position 2 showed MDR-reversing activity, along with with antimicrobial and cytotoxic effects [71]. Some antiproliferative naphthoflavones were also synthesized [34,72]. In fact, these compounds are flavones condensed with a benzene ring in positions 5 and 6, e.g., compound 59 as a xanthine oxidase inhibitor (IC₅₀ = 0.62 μM) [34]. Naphthoquinone, as a substituent, is also attached to a flavone [73]. These types of compounds were prepared via a rhodium(III)-catalyzed direct oxidative cross-coupling reaction. In the anticancer flavone–estradiol merged hybrids (60), there is a common aromatic A-ring of the flavone and the steroid in the molecule [35]. Desmoschinensisflavones A and B, having a flavonebenzylbenzoate hybrid structural framework, were isolated from Desmos chinensis Lour [74]. Some interesting flavone esters are also known; quercetin was esterified with aspirin in position 7 [75] and showed moderate anticancer activities, while chrysin was coupled with linolenic and linoleic acid on 7-OH [76], showing a competitive inhibitory effect on mushroom tyrosinase activity. Kaempferol connected with carbohydrate derivatives is known to have antibacterial effects (MIC = 0.05 µg/mL) [36]. Further chrysin derivatives were synthetized containing N,N-dimethylethylenediamine, including its carbamate (61) [77], which showed important antiproliferative activity, especially in the case of melanoma. Moreover, new hybrids were prepared by forming a 7-(3-amino-2-hydroxy-propyloxy) side chain possessing anticancer activity against prostate cancer cells [78].

3. Scope and Limitations

The potential disadvantages of hybrids are well known, i.e., high molar mass, risk of off-target toxicity, new and unexpected target recognition, and increased risk of poor solubility [79]. These compounds usually do not comply with Lipinski’s and Veber’s rules [80]. However, it is very important that some of the derivatives of flavonoids with these activities were revealed to be more potent than parent compounds or even commercially available drugs, using in vitro assays. Therefore, future exploitation of the mechanism of action underlying most potent compounds may contribute to the discovery of innovative chemotherapeutic agents.

Nevertheless, a hybridization protocol has emerged as a powerful asset for the development of more potent and less toxic drugs that exhibit increased specificity compared to conventional mono-therapy. There is substantial potential in refining and exploring novel designs, utilizing linker structures, and meticulously choosing partners and functional entities. These endeavors offer the prospect of discovering new drug candidates that could outperform existing anti-infective and anticancer medications in terms of safety and efficacy. Notably, numerous hybrid molecules have advanced through both early and late phases of clinical development, highlighting the promising role of hybridization as an innovative approach to drug discovery.

4. Conclusions

In this paper, a complete overview of the hybrids of flavones was outlined. It should be mentioned that in many cases, instead of the term “hybrid”, “derivative” seemed to be better. The characteristic families of different structures were presented, with the most typical synthetic routes; however, our most important goal was to show the biological effects. Studying all the results, it can be seen that among the effects, anticancer activity dominates in most cases. Moreover, among the compounds prepared are the most relevant structures having mitochondria-targeted characteristics and possessing MDR-modulating effects. From the evaluation of the results, it is clear how important it is that at least one of the components is a natural compound in hybrids.

Interestingly, most flavone hybrids show antiproliferative effects. Considering that cancer is still an unsolved medicinal problem all over the world, it is very important to enhance the potential role of hybrids in the treatment of cancer diseases.

Moreover, it can also be seen that the research on hybrids represents one of the possible ways of evaluating new anticancer agents.