Leader Compound Optimization Studies on 1H-Benzimidazole Derivatives for Alzheimer Disease

Çoban G. , Parlar S. , Sarıkaya G. , Tarikoğulları Doğan A. H. , Alptüzün V. , Alpan A. S.

“3rd International Multidisciplinary Symposium on Drug Research and Development (DRD2017), Erzurum, Türkiye, 5 - 07 Ekim 2017, ss.46

  • Basıldığı Şehir: Erzurum
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.46


Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder. Currently, one of the effective approaches for enhancing the cholinergic transmission is to use the acetylcholinesterase inhibitors in order to enhance the acetylcholine (ACh) concentration in the brain. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are two different types of cholinesterase that hydrolyze Ach [1]. It is known that the nitrogen atom plays a crucial role in the enzyme-compound interaction [2]. In addition, benzimidazole scaffold is the ring isoster of indanone pharmacophore of donepezil. Thus, 2-phenylsubstitue-1H-benzimidazole ring was chosen as a core structure and basic amine groups were linked to this scaffold with ethoxy chain. Due to the biological activity results, inhibitor activity of the compounds was found generally stronger against AChE than BuChE. According to molecular modeling results, some chemical modifications on the previous compounds were planned for our next study. They included the following changes: i) Due to BuChE active center being wider than that of AChE, basic amine group attached to the ethoxy side chain was replaced from para to ortho position of the phenyl moiety to increase BuChE inhibitory potency. ii) To investigate the dual binding potential, the side chain was extended in the derivatives. With this study, the results showed that ortho substituted derivatives displayed generally more active inhibitory ability than para analogues against BuChE enzyme. However, para substituted derivatives displayed strong inhibitory activity against AChE enzyme and our molecular modeling study confirmed that these analogues could combine both with the AChE central catalytic site and PAS.