Current Medicinal Chemistry - Volume 26, Issue 18, 2019

Matrix metalloproteinases (MMPs) play a key role in remodeling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation, and survival. Their importance in a variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain but only some pathological ones. Numerous neurodegenerative diseases are a consequence of or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development of these diseases. In the present review, we discuss the role of metalloproteinase inhibitors, from the wellknown natural endogenous tissue inhibitors of metalloproteinases (TIMPs) to the exogenous synthetic ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplastic diseases, the knowledge about the enzymatic system in mammalian brain tissue still remains poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of the physiological function of the adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries, and others.

Inflammation plays a crucial role in the development of many complex diseases and disorders including autoimmune diseases, metabolic syndrome, neurodegenerative diseases, and cardiovascular pathologies. Prostaglandins play a regulatory role in inflammation. Cyclooxygenases are the main mediators of inflammation by catalyzing the initial step of arachidonic acid metabolism and prostaglandin synthesis. The differential expression of the constitutive isoform COX-1 and the inducible isoform COX-2, and the finding that COX-1 is the major form expressed in the gastrointestinal tract, lead to the search for COX-2-selective inhibitors as anti-inflammatory agents that might diminish the gastrointestinal side effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs). COX-2 isoform is expressed predominantly in inflammatory cells and decidedly upregulated in chronic and acute inflammations, becoming a critical target for many pharmacological inhibitors. COX-2 selective inhibitors happen to show equivalent efficacy with that of conventional NSAIDs, but they have reduced gastrointestinal side effects. This review would elucidate the most recent findings on selective COX-2 inhibition and their relevance to human pathology, concretely in inflammatory pathologies characterized by a prolonged pro-inflammatory status, including autoimmune diseases, metabolic syndrome, obesity, atherosclerosis, neurodegenerative diseases, chronic obstructive pulmonary disease, arthritis, chronic inflammatory bowel disease and cardiovascular pathologies.

Lactate dehydrogenase (LHD) is a key enzyme of anaerobic metabolism in almost all living organisms and it is also a functional checkpoint for glucose restoration during gluconeogenesis and single-stranded DNA metabolism. This enzyme has a well preserved structure during evolution and among the species, with little, but sometimes very useful, changes in the amino acid sequence, which makes it an attractive target for the design and construction of functional molecules able to modulate its catalytic potential and expression. Research has focused mainly on the selection of modulator especially as far as LDH isozymes (especially LDH-5) and lactate dehydrogenases of Plasmodium falciparum (pfLDH) are concerned. This review summarizes the recent advances in the design and development of inhibitors, pointing out their specificity and therapeutic potentials.

Alzheimer's disease (AD) is a neurodegenerative disease that reduces progressively the part cognitive inside the Central Nervous System (CNS) and that affects the memories and emotions of the patients who endure this disease. Many drugs have been assessed in patients with different evolutionary grades of the disease, having diverse results, depending on the used compound. Some of them afford dependence and many others with side effects that affect the emotional part and the economic cost of the treatment. The natural products have diversified their therapeutic uses, and have been used in the treatment of AD in accordance with its easy medical administration and bioavailability. In this review, the use of aporphines in nature for treating Alzheimer's disease, alkaloids isolated from natural and/or synthetic sources have been used principally as cholinesterase inhibitors (acetyl- and butyrylcholinesterase) as galantamine, for instance, though its use has been questioned for being slightly effective or marginal. The use of aporphines give the possibility of generating new treatments with nitrogenous chemical structures of diverse complexity and that are focused in this review comparatively and with real therapeutic scopes.

Benzimidazole scaffold has been efficiently used for the design of various pharmacologically active molecules. Indeed, there are various benzimidazole drugs, available today, employed for the treatment of different diseases. Although there is no benzimidazole moiety containing a drug used in clinic today for the treatment of Alzheimer’s Disease (AD), there have been many benzimidazole derivative compounds designed and synthesized to act on some of the validated and non-validated targets of AD. This paper aims to review the literature to describe these benzimidazole containing molecules designed to target some of the biochemical cascades shown to be involved in the development of AD.

Tyrosinase is a multifunctional copper-containing oxidase which catalyses the oxidation of tyrosine to produce melanin. The alteration in melanin biosynthesis occurs in many diseases. The pigment has a protecting role against skin photo-carcinogenesis, but anomalous melanin pigmentation is an aesthetic problem in human beings. Moreover, the formation of neuromelanin in human brain could contribute to the neurodegeneration associated with Parkinson’s disease. Finally, tyrosinase is also responsible for undesired browning in fruits and vegetables. These topics encouraged the search for new inhibitors of this enzyme for pharmaceutical, cosmetic and foods industries. This review is to report recent trends in the discovery of tyrosinase inhibitors from plant sources, to provide a rationale for the continued study of natural tyrosinase inhibitors, and to recognise the potential therapeutic rewards associated with the identification of these agents.

The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

Background: Metal-organic frameworks (MOFs), as a new class of porous organic-inorganic crystalline hybrid materials that governed by the self-assembled of metal atoms and organic struts have attracted tremendous attention because of their special properties. Recently, some more documents have reported different types of nanoscale metal-organic frameworks (NMOFs) as biodegradable and physiological pH-responsive systems for photothermal therapy and radiation therapy in the body. Discussion: In this review paper aims at describing the benefits of using MOF nanoparticles in the field of biomedicine, and putting into perspective their properties in the context of the ones of other NPs. The first section briefly reviews the biomaterial scaffolds of MOFs. The second section presents the main types of stimuli-responsive mechanisms and strategies from two categories: intrinsic (pH, redox state) and extrinsic (temperature, light irradiation and magnetic field) ones. The combinations of photothermal therapy and radiation therapy have been concluded in detail. Finally, clinical applications of MOFs, future challenges and perspectives are also mentioned. Conclusion: This review outlines the most recent advances MOFs design and biomedical applications, from different synthesis to their use as smart drug delivery systems, bioimaging technology or a combination of both.