Current Medicinal Chemistry - Volume 22, Issue 38, 2015

Choline is a quaternary ammonium salt, and being an essential component of different membrane phospholipids (PLs) contributes to the structural integrity of cell membranes. Choline-containing phospholipids (CCPLs) include phosphatidylcholine (PC), sphingomyelin (SM), and choline alphoscerate (GPC). PC is the major phospholipid in most eukaryotic cells. It is involved in SM synthesis, choline/choline metabolite re-generation, and fatty acid/GPC formation. This paper has reviewed chemical, biological and therapeutic features of CCPLs by analyzing: a) effects of exogenous CCPLs, b) influence of GPC treatment on brain cholinergic neurotransmission, and c) neuroprotective effects of GPC alone or in association with acetylcholinesterase inhibitors in animal models of brain vascular injury, d) synthesis of the choline analogs, containing a short alkyl chain instead of a methyl group. Cytidine-diphosphocholine and GPC, protect cell membranes and could be helpful in the sequelae of cerebrovascular accident treatment. Moreover, cellular membrane breakdown is suggested as a feature of neurodegeneration both in acute (stroke) and in chronic (Alzheimer and vascular dementia) brain disorders. Published data were focused to a larger extent on the biosynthesis, relevant role in cell life, and crucial involvement of CCPLs in cholinergic neurotransmission. The possibility of their use in the treatment of cerebrovascular and neurodegenerative disorders is suggested by published clinical studies. In line with these potential practical applications in pharmacotherapy, the need of further research in the field of the synthesis of new choline derivatives with possible activity in nervous system diseases characterized by cholinergic impairment is discussed.

T helper (Th) cells belong to the adaptive immune system and provide an effective and antigen-specific means of host protection. Th17 cells are a subset of Th cells, characterized by the production of the inflammatory cytokines interleukin (IL)-17A (IL-17A) and IL-17F, which bind to a receptor complex comprised of IL-17RA and IL-17RC subunits. Th17 cells combat extracellular and fungal infections, but have been implicated in autoimmune diseases. In many autoimmune conditions, the dysregulated immune response involves several parts of the immune system, including autoantibodies, B and T cells. Targeted biological therapies are appealing, as they may prevent unwanted side effects in patients. There is evolving evidence that Th17 cells are important in the kidney, mediating injury in response to vascular or chemical insults to the renal tubules, and in autoimmune diseases of the glomerulus, either through a specific attack on the glomerular basement membrane or as part of a generalized systemic inflammatory disease. Therapies targeting IL-17A, IL-12p40 and IL-17RA are being explored in clinical trials or are being utilized in clinical practice for the treatment of other IL-17 mediated diseases, such as psoriasis. This review explores the current evidence that IL-17A and Th17 cells may be pathogenic in immune kidney disease, including anti-glomerular basement membrane disease, antineutrophil cytoplasmic antibody associated vasculitis and lupus nephritis, as well as in acute kidney injury. It will discuss the place that biological agents against IL-17A, IL-12p40 and IL-17RA may have in the treatment of these conditions.

Ion channel dysfunction has been identified as a contributor to symptom development and neurodegeneration in multiple sclerosis (MS). The molecular insights have been translated into new lines of research, with ion channel modulation now representing a therapeutic approach in MS. Studies of Na+ channel function have demonstrated pathological blockade of Na+ channels during an acute inflammatory attack. Relapses are typically associated with subsequent alterations in Na+ channel expression and structure. However, these compensatory changes may also be deleterious. Specifically, increased Na+ channel expression may contribute to neuronal energy insufficiency and a cascade of events that may ultimately lead to neurodegeneration and apoptosis. Pharmacological blockade of Na+ channels in animal models of MS demonstrated encouraging results, although mixed results were obtained in subsequent clinical trials in MS patient cohorts. The process involved in demyelination, a characteristic event in MS pathology, may also induce complex structural changes mediated by K+ channels that may in turn hinder neural transmission. From a therapeutic perspective, the potent K+ channel blocker, 4-aminopyridine (4-AP), has demonstrated neurophysiological and functional improvements in animal models of demyelination. Clinical translation of these results was recently achieved with the advent of Fampridine PR, a modified release form of 4-AP, with phase III clinical trials that demonstrated improvement in neurological symptoms including fatigue, walking speed and strength in MS patients.

TB drug development pipeline represents varied structural classes of molecules. Oxazolidinones represent synthetic anti-bacterial agents with unique mechanism of action having wide spectrum of activity, oral bioavailability and well established SAR. They act by inhibiting translation at the initiation phase of protein synthesis. Linezolid was the first oxazolidinone to reach the market in the year 2000 for the treatment of methicillin-resistant staphylococcal and vancomycin-resistant enterococcal infections. Oxazolidinones have shown very good anti-mycobacterial activities. Several oxazolidinones are currently in development for their possible use in TB therapy. Oxazolidinones are classified on the basis of C-ring modifications. DuP-721 was the first oxazolidinone having good anti-TB activity. Linezolid, sutezolid and AZD5847 are in clinical development. Several other C-ring modifications have shown promising results. The usefulness of these oxazolidinones in the drug resistant TB is already established. Toxicity, especially myelosuppression, has been an important limiting factor for their development.

Curcumin, a natural phenolic compound mainly extracted from turmeric curcuma longa, has been employed to prevent or treat plenty of diseases particularly cancer. It has been proven to modulate various signal transduction pathways and exhibits antiinflammatory, anti-oxidative, anti-metastasis anti-proliferative, anti-angiogenic in addition anti-cancer activities. However, its poor solubility and rapid degradation severely hampers the introduction into clinical setting. In this review, we focus on the design of polymeric micelles (PMMCs) which are nano-scaled drug delivery vehicles and fabricated from biocompatible polymers for efficient curcumin delivery. In particular, recent progress of curcumin loaded internal stimuli responsive PMMCs for further intracellular uptake via internal triggers is also discussed.

Bisindolylmethane and its derivatives are pharmacologically active and applicable in the field of pharmaceutical chemistry. Bisindolylmethanes have a variety of biological activities such as antihyperglycemic, antiinflammatory, antibacterial, anticancer, and antileishmanial activities, including enzyme inhibition activity. They play a crucial role in many diseases especially anticancer activity. Modifying their structure had proven to be useful in the search of new therapeutic agents. Extensive research carried out on bisindolylmethane and its derivatives shows that they are pharmacologically significant. The present review focuses on the pharmacological profile of bisindolylmethane derivatives. This review includes the current literature with an update of research findings as well as the perspectives that they hold for future research.