# Carbazoles: Role and Functions in Fighting Diabetes
## 2 Carbazole Derivatives in the Pathogenesis of Diabetes
### Carvedilol  
The carbazole derivative **1** (carvedilol, 1-(9_H_-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy) ethylamino]propan-2-ol) (Figure 3), synthesized by the reaction of 4-(oxirane 2-ylmethoxy)-9_H_-carbazole with 2-(2-methoxyphenoxy)ethylamine [47], was discovered in a study devoted to discovering agents useful in the treatment of congestive heart failure. The interaction of carvedilol (**1**) with beta-adrenergic receptors is stereospecific, in a similar way that was demonstrated for carazolol, a veterinary medicine drug used to reduce stress in animals during transport [48]. This optically active compound exhibits activity as a selective beta-adrenergic receptor blocker such as the \(S\) (\(-\)) enantiomer, whereas the \(R\) (+) enantiomer is capable of antagonizing both alpha-1 and beta-adrenergic receptors. These characteristics make this molecule more effective than other traditional beta-blockers in the treatment of heart failure and in the regulation of myocardial functions. Furthermore, unlike other beta-blockers, it does not cause alterations in the metabolism of carbohydrates and lipids [49]. Carvedilol (**1**) was found to reduce insulin resistance by increasing the sensitivity of insulin receptors (IRs) and by reducing the activity of the sympathetic nervous system [50]. The adrenergic system, in part through beta-2 adrenergic receptors, regulates glucose and lipid metabolism in the liver, adipose tissue, and skeletal muscle. Taking into consideration all these properties, several studies were focused on the evaluation of the efficacy of carvedilol (**1**) in preventing heart complications in patients with diabetes [7; 51; 52; 53]. In an earlier study on the efficacy and tolerability of long-term \begin{table}
\begin{tabular}{l l l l} \hline \hline \multicolumn{1}{c}{**Compound**} & \multicolumn{1}{c}{**Name**} & \multicolumn{1}{c}{**Biological Activity**} & \multicolumn{1}{c}{**References**} \\ \hline
**18** & Koenidine & Antidiabetic activity in L6-GLUT4 myc & [42] \\ (Naturalcompound) & 8,9-Dimethoxy-3,3,5-trimethyl-11_H_-pyrano & myotubes & \\  & &
\begin{tabular}{l} Increase in insulin sensitivity and \\ progressive reduction of blood glucose \\ level \\ \end{tabular} & \\ \hline
**19** & Mahanimbine & Antidiabetic activity in L6-GLUT4 myc & [42] \\ (Naturalcompound) & 3,5-Dimethyl-3-(4-methylpent-3-enyl)-11_H_-pyrano[3,2-_a_]carbazole & myotubes & \\ \hline
**20** & Murrayazoline & Antidiabetic activity in L6-GLUT4 myc & [42] \\ (Naturalcompound) & (14\(R\),175,195)-3,13,13,17-Tetramethyl-21-oxa-12-azahexacyclol[10.7.1.12\({}^{,}\)17.05\({}^{,}\)20.06\({}^{,}\)11.0\({}^{,}\)14\({}^{,}\)19] &henicosa- \\  & 1,3,5(20),6,8,10-hexa & \\ \hline
**21** & (S)-3-(4-(2-9_H_-Carbazol-9-yl)ethoxy)phenyl)-2-ethoxypropanoic acid & Improve of the insulin sensitivity & [43] \\ \hline
**22** & Chigltazar & Reduction of glycosylated hemoglobin A1c & [44; 45; 46] \\ (Synthetic compound) & (2_S_)-3-[4-(2-Carbazol-9-ylethoxy)phenyl]-2-[2-(4-fluorophenylobenzoyl)]-2-[2-(4-acid) & Hypoglycemic effect \\  & diwobenzoyl)anillion]propanoic acid & Increase in insulin sensitivity & \\  & acid & Reduction of triglycerides & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: _Cont._  
Figure 3: Structure of carvedilol (**1**). administration of carvedidol (**1**), [PERSON] et al. [27] evaluated the drug's effects in patients with chronic heart failure, a number of whom were also diabetic. Treatment with increasing doses of carvedidol was well tolerated by all treated patients, showing positive effects on left ventricular function and on resting and exercise hemodynamics. Furthermore, unlike traditional beta-blockers, it did not affect insulin sensitivity and glycemic values in diabetic patients treated with oral hypoglycemic agents or insulin [27; 54; 55].