# Recent Updates on the Synthesis of Bioactive Quinoxaline-Containing Sulfonamides
## 2 Synthesis and Biological Activities
### Synthesis of Quinoxaline Moiety-Based Benzene Sulfonamides with Antitumor Activity  
A mass or lump of tissue that is formed by an accumulation of abnormal cells, resembling swelling and varying from a tiny nodule to a large mass, is specified as a tumor. Not all tumors are cancerous; some are benign (non-cancerous), premalignant (having potential to become cancerous) and some are malignant (cancerous). A chemotherapeutic agent which has the ability to prevent or inhibit the formation or growth of tumors is termed as antitumor.  
[PERSON] et al. developed a novel synthetic strategy to furnish novel sulfamoyl phenyl carbamoyl quinoxaline hybrid structures. In the first step, quinoxaline-2,3-dicarboxylic  
Figure 13: Structure of quinoxaline-1,4-dioxide sulfonamide derivatives **90–92**.  
\begin{table}
\begin{tabular}{c c} \hline \hline \multicolumn{3}{c}{**Antileishmanal Activity**} \\ \hline
**Compound** & **IC\({}_{50}\) (uM)** \\ \hline
90 & 20.3 \\
91 & 16.3 \\
92 & 3.1 \\ Amphotericin B & 0.2 \\ \hline \hline \end{tabular}
\end{table}
Table 8: Antileishmanal activity of quinoxaline-1,4-dioxide sulfonamide derivatives **90–92**.  
acid **94** was produced by the treatment of OPD 34 with disodium dihydroxytarratrate **93**, followed by a reaction with acetic anhydride, which resulted in the formation of quinoxaline anhydride derivative **95**. The scaffold 95 was refluxed with substituted sulfonamide **96** in ethanol to afford 3-sulfamoyl phenylcarbamoyl quinoxaline-2-carboxylic acids **97** at 71-78% yield, which further reacted in quinoline-containing copper powder to obtain corresponding quinoxaline sulfonamide scaffold **98**. The quinoxaline sulfonamide derivative **98** was also prepared at 68-73% yield by directly heating the anhydride compound **95** with sulfonamide compound **96** under fusing conditions (Scheme 9) [135].  
The quinoxaline sulfonamide derivative **99** displayed the most potent antitumor activity against the liver carcinoma cell line (IC\({}_{50}\) value 0.5 \(\upmu\)g m/L), while moderate anti-tumor activity was exerted by **100** (IC\({}_{50}\) value 4.75 \(\upmu\)g m/L, Table 9). The quinoxaline sulfonamide structural motif **101** demonstrated the least antitumor activity, exhibiting an IC\({}_{50}\) value of 6.79 \(\upmu\)g m/L. The SAR described that the presence of a carboxylic acid group on the quinoxaline was responsible for the potent antitumor activity of **99**, while its absence in **100** led to a moderate activity. The absence of the isoxazole in **101** produced the worst action herein (Figure 14) [135].  
[PERSON] and coworkers reported the synthesis of new anticancer quinoxaline sulfonamide derivatives. The 2,3-diphenylquinoxaline derivative **56** was treated with electrophilic compound **47** to produce 2,3-diphenyl quinoxaline-6-sulfonylchloride **57** that further refluxed with primary amines in a basic medium and resulted in the formation of the desired final product, substituted quinoxaline sulfonamides **58** at 53-78% yield (Scheme 10) [136].  
These synthesized quinoxaline sulfonamide derivatives were tested for their cytotoxicity in vitro against various cancer cell lines, such as leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer cell lines. Among all the synthesized derivatives, the chlorophenyl-containing moiety quinoxaline sulfonamide **103** and the pyridine moiety-containing quinoxaline sulfonamide **104** (Figure 15) exhibited the greatest anticancer activities against various above mentioned cancer cell lines [136].  
Figure 14: Substituted quinoxaline sulfonamide derivatives **99–101**.  
\begin{table}
\begin{tabular}{c c} \hline \hline \multicolumn{2}{c}{**Antitumor Activity**} \\ \hline
**Compound** & **IC50** (**ug m/L**) \\ \hline
**99** & 0.5 \\
**100** & 4.75 \\
**101** & 6.79 \\ \hline \hline \end{tabular}
\end{table}
Table 9: Anti-tumor activity of quinoxaline sulfonamides **99–101**.