Development of novel N-(6-methanesulfonyl- benzothiazol-2-yl)-3-(4-substituted-piperazin-1- yl)-propionamides with cholinesterase inhibition, anti-b-amyloid aggregation, neuroprotection and cognition enhancing properties for the therapy of Alzheimer's disease† Chandra Bhushan Mishra,‡ a Shruti Shalini,‡ a Siddharth Gusain, a Amresh Prakash, b Jyoti Kumari, a Shikha Kumari, a Anita Kumari Yadav, a Andrew M. Lynn c and Manisha Tiwari * a A novel series of benzothiazole–piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). The synthesized hybrid molecules illustrated modest to strong inhibition of acetylcholinesterase (AChE) and Ab 1-42 aggregation. Compound 12 emerged as the most potent hybrid molecule exhibiting balanced functions with effective, uncompetitive and selective inhibition against AChE (IC 50 ¼ 2.31 mM), good copper chelation, Ab 1-42 aggregation inhibition (53.30%) and disaggregation activities. Confocal laser scanning microscopy and TEM analysis also validate the Ab fibril inhibition ability of this compound. Furthermore, this compound has also shown low toxicity and is capable of impeding loss of cell viability elicited by H 2 O 2 neurotoxicity in SHSY-5Y cells. Notably, compound 12 significantly improved cognition and spatial memory against scopolamine- induced memory deficit in a mouse model. Hence, our results corroborate the multifunctional nature of novel hybrid molecule 12 against AD and it may be a suitable lead for further development as an effective therapeutic agent for therapy in the future. 1. Introduction Alzheimer's disease (AD) is a predominant source of irreversible dementia, resulting in more than 75% of the dementia cases worldwide. It is known to be a multifactorial neurodegenerative disorder designated by progressive loss of memory and other cognitive functions. The main risk factor of AD is aging; however the mechanism underlying the foundation of AD due to aging is yet to be rmly elucidated. It is clinically marked by the progression from episodic memory problems to a slow global decline of cognitive function. Patients in end-stage AD become bedridden and are highly dependent on custodial care, with an average life span of 9 years aer diagnosis. 1 AD leaves an enormous emotional and nancial burden on patients, their families and society. There are approximately 44 million people affected by Alz- heimer's disease, and it is expected to increase three times by 2050; these perturbing numbers show that Alzheimer's disease (AD) remains a serious socio-economical problem. 2 AD is esti- mated to have cost the world $604 billion in 2010 alone. 3 These costs are staggering, particularly in light of worldwide increase in the number of AD cases. AD remains the most prevalent unmet medical need because of its chronicity, cost, severity, and lack of mechanism based treatment. 4 Extensive research from several years has still not been able to establish the exact molecular-mechanistic aspects of AD. Clinically, AD is indicated by widespread neuronal cell death in the brain, which corresponds to deposition of abundant brillar plaques, primarily comprising the beta-amyloid (Ab) peptide. 5,6 The identied pathological hallmarks of AD are senile plaques of amyloid beta protein, intracellular neurobrillary tangles (NFTs), and neuronal degeneration. Accumulation of Ab peptides encourages conformational changes that lead to further non-covalent polymerization into a heterogeneous a Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi 110007, India. E-mail: mtiwari07@gmail.com b Amity Institute of Integrative Sciences and Health (AIISH), Amity University Haryana, Amity Education Valley, Gurgaon-122413, India c School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India † Electronic supplementary information (ESI) available: In silico study data, 1 H and 13 C spectra of all synthesized compounds have been kept as supplementary data. See DOI: 10.1039/d0ra00663g ‡ These authors contributed equally to this work. Cite this: RSC Adv. , 2020, 10, 17602 Received 21st January 2020 Accepted 19th April 2020 DOI: 10.1039/d0ra00663g rsc.li/rsc-advances 17602 | RSC Adv. , 2020, 10, 17602–17619 This journal is © The Royal Society of Chemistry 2020 RSC Advances PAPER Open Access Article. Published on 05 May 2020. Downloaded on 7/1/2020 12:29:44 AM. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. View Article Online View Journal | View Issue