Aryldiazoquinoline based multifunctional small molecules for modulating Ab 42 aggregation and cholinesterase activity related to Alzheimer's disease† Monika Rana, a Abhishek Pareek, b Shivani Bhardwaj, a Geeta Arya, c Surendra Nimesh, c Hemant Arya, c Tarun K. Bhatt, c Srinivasarao Yaragorla * b and Anuj K. Sharma * a Research continues to find a breakthrough for the treatment of Alzheimer's Disease (AD) due to its complicated pathology. Presented herein is a novel series of arydiazoquinoline molecules investigated for their multifunctional properties against the factors contributing to Alzheimer's disease (AD). The inhibitory properties of fourteen closely related aryldiazoquinoline derivatives have been evaluated for their inhibitory effect on Ab 42 peptide aggregation. Most of these molecules inhibited Ab 42 fibrillation by 50–80%. Selected molecules were also investigated for their binding behaviour to preformed Ab 40 aggregates indicating a nanomolar affinity. In addition, these compounds were further investigated as cholinesterase inhibitors. Interestingly, some of the compounds turned out to be moderate in vitro inhibitors for AChE activity with IC 50 values in low micro molar range. The highest anti-AChE activity was shown by compound labelled as 2a with an IC 50 value of 6.2 mM followed by 2b with IC 50 value of 7.0 mM. In order to understand the inhibitory effect, binding of selected molecules to AChE enzyme was studied using molecular docking. In addition, cell toxicity studies using Neuro2a cells were performed to assess their effect on neuronal cell viability which suggests that these molecules possess a non-toxic molecular framework. Overall, the study identifies a family of molecules that show good in vitro anti-Ab- aggregation properties and moderately inhibit cholinesterase activity. 1. Introduction Alzheimer's disease (AD), the most common cause of dementia, affects around 50 million people worldwide. Its prevalence is expected to double every 20 years, rising to more than 130 million by 2050. Impact in countries varies with the proportion of elderly individuals in the population. 1 In the absence of an effective treatment for this, AD remains one of the most feared consequences of aging and requires better diagnostic tools, management and effective therapies. 2–5 The aetiology of AD is very complicated. Several pathological factors such as loss of acetylcholine (ACh) and butyrylcholine (BuCh) neurotransmitters, amyloid beta (Ab) aggregation into toxic oligomers and plaques, metal ion dyshomeostasis and oxidative stress etc. are suggested for AD pathogenesis. 5–12 The classical amyloid cascade hypothesis suggests that the most important contributor to AD is amyloid plaques which are deposits of Ab peptide aggregates. 13–15 However, recent studies suggest that in addition to the plaques, smaller soluble aggre- gates of Ab peptides are much more neurotoxic. 16–19 Molecules that reduces the aggregation of Ab peptides and formation of such neurotoxic species are in demand. 7 Several inhibitors of Ab aggregation are reported in literature; some of these inhibitors lead to soluble neurotoxic oligomers and some to non-toxic aggregates. 2,18,20–22 On the other hand, inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) to protect acetylcholine in AD patients has been the most attractive therapeutic strategy. The cholinesterase (ChE) enzymes AChE and BuChE are responsible for the hydrolysis of acetylcholine. 23,24 Tacrine and donepezil based scaffolds are so far the most potent type of AChE and BuChE inhibitors. 25,26 However, alternative molecular scaffolds (e.g., coumarins, quinolines, xanthones etc.) are also known to inhibit AChE and BuChE, albeit with lower potency. 27–29 a Department of Chemistry, Central University of Rajasthan, NH-8, Bandarsindri, Ajmer, Rajasthan, 305817, India. E-mail: anuj.sharma@curaj.ac.in; aks.iitk@gmail. com b School of Chemistry, University of Hyderabad, P.O. Central University, Hyderabad, 5000046, Telangana State, India. E-mail: Srinivas.yaragorla@uohyd.ac.in c Department of Biotechnology, Central University of Rajasthan, NH-8, Bandarsindri, Ajmer, Rajasthan, 305817, India † Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra05172a Cite this: RSC Adv. , 2020, 10, 28827 Received 12th June 2020 Accepted 22nd July 2020 DOI: 10.1039/d0ra05172a rsc.li/rsc-advances This journal is © The Royal Society of Chemistry 2020 RSC Adv. , 2020, 10, 28827–28837 | 28827 RSC Advances PAPER Open Access Article. Published on 04 August 2020. Downloaded on 10/14/2021 12:10:18 PM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue