Coumarins are a very large family of compounds containing the unique 2H-chromen-2-one motif, as it is known according to IUPAC nomenclature. Coumarin derivatives are widely found in nature, especially in plants and are constituents of several essential oils. Up to now, thousands of coumarin derivatives have been isolated from nature or produced by chemists. More recently, the coumarin platform has been widely adopted in the design of small-molecule fluorescent chemosensors because of its excellent biocompatibility, strong and stable fluorescence emission, and good structural flexibility. This scaffold has found wide applications in the development of fluorescent chemosensors in the fields of molecular recognition, molecular imaging, bioorganic chemistry, analytical chemistry, materials chemistry, as well as in the biology and medical science communities. This review focuses on the important progress of coumarin-based small-molecule fluorescent chemosensors during the period of 2012-2018. This comprehensive and critical review may facilitate the development of more powerful fluorescent chemosensors for broad and exciting applications in the future.

Coumarin-Based Small-Molecule Fluorescent Chemosensors.

Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression. According to the "Amyloid Cascade Hypothesis" the critical molecular event in the pathogenesis of AD is the accumulation of Aβ neurotoxic oligomers. Since the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) is the rate-limiting step in the production of Aβ, this enzyme is considered a major therapeutic target and BACE1 inhibitors have the potential to be disease-modifying drugs for AD treatment. Therefore, intensive efforts to discover and develop inhibitors that can reach the brain and effectively inhibit BACE1 have been pursued by several groups worldwide. The aim of this review is to highlight the progress in the discovery of potent and selective small molecule BACE1 inhibitors over the past decade.

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Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

The chemistry and biology of guanidine natural products

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies.

/pdf/tau-post-translational-modifications-dynamic-transformers-of-ge62lzz74b.pdf

Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression.

Astrocytes, the star shaped glial cells, are known to possess supportive and homeostatic role for the neurons. Recently, reactive gliosis, which involves alterations in functioning and phenotype of different glial cells, has been implicated in Alzheimer's Disease (AD). Studies have revealed that astrocyte response to gross tissue damaging injury leads to anisomorphic astrogliosis reinforcing a cascade of events, eventually increasing the pathogenesis of AD and many other neurodegenerative disorders. This review presents the involvement of reactive astrocytes in reduced Aβ clearance and in neuro-neglect hypothesis. Understanding of reactivity and fundamental biology of astrocytes may open new avenues of alternative treatments and therapeutic strategies targeting astrocytes and related events for the treatment of AD.

Reactive Astrogliosis: Role in Alzheimer's Disease.

β-Secretase (BACE-1) is an important and attractive target involved in the pathogenesis of Alzheimer’s disease (AD). The enzyme is involved in the cleavage of amyloid precursor protein (APP) which is the rate-limiting step for the production of Aβ-42. β-Secretase inhibitors inhibit the amyloidogenic cleavage of APP and hence prevent the synthesis of Aβ-42, the cause of AD. A data set of aminoimidazoles was used to study the two-dimensional quantitative structure activity relationships (2D-QSAR) to explore the structural requirements for BACE-1 inhibition. This series of molecules is known to possess BACE-1 inhibitory activity in vivo. 2D-QSAR models were developed using multiple linear regression analysis which were then validated using leave-one-out method. The selected QSAR model displayed significant relationship between descriptors and biological activity along with internal and external predictivity. The developed model was also validated using external data set of hydantoins. The study reveals that thermo-dynamic descriptors (molar refractivity, Log P, van der Waals energy, polar surface area) and steric descriptors (Harary index, Randic index) play important role in β-secretase inhibition. The information generated may be useful for the design of novel and potent β-secretase inhibitors.

Quantitative structure activity relationship analysis of aminoimidazoles as BACE-I inhibitors

Advances in the colon-targeted chitosan based multiunit drug delivery systems for the treatment of inflammatory bowel disease.

Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer's disease as it is involved in tau phosphorylation. Due to its high specificity concerning substrate recognition, GSK3 has been considered as an important target. In the last decade, several GSK3 inhibitors have been reported and two molecules are in clinical trials. This review collates the information published in the last decade about the role of GSK3 in Alzheimer's disease and progress in the development of its inhibitors. Using this collated information, medicinal chemists can strategize and design novel GSK3 inhibitors that could be useful in the treatment of Alzheimer's disease.

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors.

Human Immunodeficiency Virus Type 1 Integrase or HIV-1 integrase(IN) is a 288 amino acid protein that incorporates the retrotranscribed viral DNA into the host chromosomal DNA. Over the past 30 years, large number of derivatives have been evaluated for their inhibitory potential against IN. There is vast literature available and needs to be collated to help scientists plan the future drug design. This review discusses the reports of past 25 years on analogues of quinoline, coumarin and other related heterocycles, which exhibit low micromolar inhibitory potency against IN.

Priti Jain

Papers

Reactive Astrogliosis: Role in Alzheimer's Disease.

Quantitative structure activity relationship analysis of aminoimidazoles as BACE-I inhibitors

Advances in the colon-targeted chitosan based multiunit drug delivery systems for the treatment of inflammatory bowel disease.

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors.

Quinoline, Coumarin and Other Heterocyclic Analogs Based HIV-1 Integrase Inhibitors.