Author ORCID Identifier

Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Shijun Zhang


Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting ~5.2 million Americans. Current FDA approved medications provide mainly symptomatic relief and there are no agents available to delay or cure this disease. Multiple factors such as amyloid-β aggregates, dyshomeostasis of biometals, oxidative stress, and neuroinflammation have been implicated in the development of AD. Even though significant advances have been made in understanding the mechanisms leading to AD, the exact etiology still remains elusive. Given AD’s multifactorial nature, a multifunctional strategy of small molecule design would help to identify novel chemical templates. Recently our lab has developed hybrid molecules of curcumin and melatonin that exhibited potent neuroprotective ability in various AD models. Further modifications identified a lead compound with potent neuroprotective and antioxidative activity in MC65 cells, while also establishing the hybrid strategy as a viable approach in providing unique chemotypes with novel pharmacology. Further preliminary biological studies suggest that the lead is orally available and exhibits multifunctional properties both in vitro and in vivo on AD pathologies, thus strongly encouraging further structural examination. Herein, we report the structural exploration of this chemical template through structure-activity relationship studies at three domains: the phenyl domain, α,β-unsaturated β-ketone amide domain, and the indole domain. Collectively, the results show that the chemical space around the curcumin portion doesn’t favor electronic or steric/hydrophobic interactions, but might favor pi-pi (π-π) and hydrogen-bond interactions. Additionally, the α,β-unsaturated β-ketone amide domain is not as important as the linearity of the β-ketone acetamide. Moreover, the results indicate that a free rotatable β-OH might be the actual moiety that is important for the observed biological activity through favorable hydrogen bonds. Finally, steric interactions are not favored in the chemical space surrounding the indole nitrogen, suggesting that hydrogen bond interactions are required for the observed neuroprotective activity. Conversely, a hydrogen bond acceptor is necessary at the 5-position of the indole ring and bulky substitutions can be accommodated, with restrictions, suggesting steric tolerance and hydrophobic interactions at this position. These modifications have yielded a series of novel compounds that are capable of modifying AD pathology while shedding further light onto the chemical scaffold thus warranting future investigations into the development, optimization, and characterization of these curcumin/melatonin hybrids as potential treatments for AD.


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Available for download on Sunday, December 05, 2021