Computer Aided Design, Synthesis and Biological Evaluation of Certain Small Organic Molecules

Abstract

Targeting protein-protein interactions (PPI) has always been considered a great challenge for medicinal chemists. The discovery of inhibitors for the bromodomains is considered an excellent opportunity for targeting PPI. Bromodomain (BRD) is one of the epigenetic readers that can recognize and bind to the acetylated lysine (Kac). There are 61 different BRDs in human found in 46 proteins that are clustered in 8 families. Bromodomain and extra terminal domain (BET) family is the most important. Inhibition of BET is found to be a therapeutic approach for many human disorders like COPD, atherosclerosis, inflammatory disorders, some viral infections and cancer. Since the discovery of the first two potent selective inhibitors (JQ1 and I-BET762), different research groups were trying to optimize, design and develop new more potent and selective inhibitors. In the current study, 1,2,5-trisubstituted-benzimidazole belonging to two series: 1-cyclohexyl-2-phenyl-5-substituted-benzimidazoles and 1-cyclohexyl-5-oxadiazolyl-2-substituted-benzimidazoles, were designed and synthesized as selective BET inhibitors. We used the SAR studies and bioisosteric modification of lead compounds. Moreover, we explored the binding site using molecular modeling techniques to design our new inhibitors. Synthesis of the designed compounds was then acheived & their structures were verified by various spectral and microanalytical data.