Diabetic cardiomyopathy is a clinical condition diagnosed when ventricular dysfunction develops in patients with diabetes devoid of coronary atherosclerosis and hypertension. The selective inhibition of PKCβII represents an effective approach for treating microvascular complications. HQSAR and CoMSIA studies were performed on a data set of 43 maleimide-based molecules acting as potent inhibitors of PKCβII. HQSAR model yielded an of 0.98 and a cross-validated of 0.85, while CoMSIA modeling of these same data generated an of 0.98 and a cross-validated of 0.85. Both the models show good predictive power having for HQSAR and CoMSIA as 0.63 and 0.75, respectively, indicating the reliability of models. The analysis shows that the terminal substitution with electronegative atom at indole or azaindole ring is essential for PKCβII inhibition, while substitution of bulkier group in linker connecting two heteroaryl rings diminishes the activity. This study is presumably helpful in designing new potent molecules as PKCβII inhibitors in fighting against various diseases related to PKCβII.