OVERVIEW Natural products and their derivatives as multifunctional ligands against Alzheimer's disease Pooja Patil 1,2 | Ashima Thakur 1 | Abha Sharma 1 | Swaran Jeet Singh Flora 1 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, Uttar Pradesh, India 2 Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow, Uttar Pradesh, India Correspondence Abha Sharma and Swaran Jeet Singh Flora, Department of Medicinal Chemistry and Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow Campus, Sarojini Nagar, Lucknow 226 002, UP, India. Email: sjsflora@hotmail.com; abha.sharma@niperraebareli.edu.in Abstract Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular changes including impaired cholinergic system, beta-amyloid (βA) aggregation, tau hyper- phosphorylation, metal dyshomeostasis, neuroinflammation, and many other pathways are involved in the pathogenesis of the disease. However, the exact cause of the disease is not known. Natural products such as flavonoids, alkaloids, resveratrol, and curcumin have multifunctional properties, and have drawn the attention of the researchers because these molecules are capable of interacting concurrently with the multiple targets of AD. Therefore, natural products and their derivatives with proven efficacy could be used in the management of the neurodegenerative disorders. This review focuses on the natural product based multitarget directed ligands like tacrine-coumarin, tacrine-huperzine A, harmine-isoxazoline, berberine-thiophenyl, galantamine-indole, pyridoxine-resveratrol, donepezil-curcumin and their mode of action. KEYWORDS Alzheimer's, alkaloid, flavonoid, multitarget ligand 1 | INTRODUCTION Alzheimer's disease (AD) was discovered by Dr. Alois Alzheimer in 1906, which is an age-related progressive, chronic, and irreversible neurodegenerative disease. In AD, cortex and hippocampus are affected, which leads to progressive memory loss, cognitive and lan- guage impairment that usually starts slowly and gets worse over time. The common early symptom is short-term memory loss and with the progression of the disease, some other problems are visible including disorientation, lack of self-care, lose the ability to communicate, behavioral issues, mood swings, and motivational loss. In the final stage of the disease, condition of the patient gets worse, withdraws himself/herself from the family and society and eventually leads to paralysis and death (Alzheimer's Association, 2017). The actual cause of AD is not clearly understood. However, causes could be genetic, history of head injuries, depression, or hypertension that facilitates pathogenesis (Li et al., 2017; Van der Mussele et al., 2014). Early symptoms of AD are considered as the early signs of normal aging. The apparent changes observed in AD patient's brain are the formation of an extracellular accumulation of senile plaques and intra- cellular neurofibrillary tangles. There are no medications for the cure and halting the progression of AD. Existing drugs only temporarily relieve symptoms by either inhibiting the enzyme acetylcholinesterase or antagonize N-methyl-D-aspartate receptor. Consequently, treat- ment fails and eventually cognitive function of the patient deterio- rates (Van der Mussele et al., 2014). However, the development of more efficacious therapies for AD is challenging because of complex etiology. Many newly designed molecules have entered clinical trials but their failure has made researchers to reexamine the etiology of AD. The multifaceted nature of AD suggests for synthesizing multifunctional molecules which are capable of interacting with multi- ple targets. In this direction, designing multitarget directing ligands (MTDLs) has gained attention for the development of novel molecules against AD. Using the MTDL strategy, a variety of hybrid compounds targeting more than one pathway involved in AD pathogenesis has been reported (Savelieff et al., 2018). This review highlights some recent advances in development of natural products based MTDLs as promising drug candidates for the treatment of AD. Received: 20 December 2018 Revised: 2 July 2019 Accepted: 22 July 2019 DOI: 10.1002/ddr.21587 Drug Dev Res. 2019;1–19. wileyonlinelibrary.com/journal/ddr © 2019 Wiley Periodicals, Inc. 1