# Flavone Hybrids and Derivatives as Bioactive Agents
## 2 Flavone Hybrids with Different Pharmacophores
### Hybrids with 1,2,3-Trizzoles and Their Derivatives
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 \(IC_{50}\) = 5.9 \(\upmu\)M 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 antimyobacterial 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. Figure 4: Bis-substituted and aryltriazolezolyl chrysin hybrids. Figure 3: Synthesis of chrysin hybrids with benzyl-substituted 1,2,3-triazole. Some of the compounds (**11**) showed moderate antiproliferative activity on cell line MCF-7 of breast cancer (\(IC_{50}\) = 14.5-19.1 \(\mu\)M), and hybrid **9** (R=CH\({}_{3}\), R\({}^{1}\)=H) showed moderate antim mycobacterial 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 \(GI_{50}\leq 0.01\)\(\mu\)M 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). Figure 5: 7-Hydroxylavones coupled with heterocycles. Figure 6: Synthesis of aminoflavone hybrids with substituted 1,2,3-triazole. 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 (\(IC_{50}=10\) uM) 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 \(3^{\prime}\)-azido-\(2^{\prime}\)-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].