Mini Reviews in Medicinal Chemistry - Volume 6, Issue 11, 2006

Quinoxaline derivatives have received much attention in recent years owing to their both biological properties and pharmaceutical applications. In this review we focus the attention on quinoxalin-2(3)-ones and quinoxalin-2,3-diones. These derivatives are particularly interesting since some of them showed antimicrobial (against several bacteria, viruses, fungi, etc), or anticancer activities. Furthermore, others are reported to be potent no-NMDA glutamate receptor antagonists, endowed with anxiolytic, deconditioning, analgesic, antispastic, antiallergic, antithrombotic activities. In this article we also report SAR studies and the most important methods of synthesis of the quinoxalin-2(3)-(di)ones.

This review summarizes the knowledge of the role of dietary PUFAs, especially ω-3, on normal brain function. Furthermore, it reports the evidence pointing to potential mechanisms of ω-3 fatty acids in development of neurological disorders and efficacy of their supplementation in terms of symptom management.

Adenosine-to-Inosine RNA editing introduces changes in RNA transcripts via a post-transcriptional mechanism, the hydrolytic deamination of adenosine (A) to inosine (I) which is interpreted as guanosine by cellular machineries. Adenosine deaminases that act on RNA (ADAR) enzymes catalyze editing in double-stranded (ds) RNA substrates.

The molecular scaffold is an oft-cited concept in medicinal chemistry suggesting that the definition of what makes a scaffold is rigorous and objective. However, this is far from the case with the definition of a scaffold being highly dependent on the particular viewpoint of a given scientist. It follows, therefore, that the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. These techniques are adapted from chemoinformatics to be applied in the design of new medicinal compounds.

The increasing drug resistance of malaria parasites against chemotherapeutics enforces new strategies in finding new drugs. Here, we describe a new class of compounds the piperidone 3-carboxylates which show an antiplasmodial effect in vitro and in vivo. This effect might be caused by inhibition of eukaryotic initiation factor (eIF-5A).

Adverse extracellular matrix (ECM) remodeling contributes to fibrotic disorders in the kidney, lung, and heart. Matrix metalloproteinases (MMPs) are key enzymes regulating ECM turnover, and MMP inhibition attenuates remodeling. Recent technological developments allow MMP-substrate relationships to be identified and explored as novel therapeutic targets. This review summarizes current and novel strategies to block MMP activity.

NKT cells are a subset of regulatory lymphocytes characterized by co-expression of the NK cell receptor- CD161 and an invariant TCR-α chain (Vα14-Jα28). They are most abundant in the liver, spleen, and bone marrow. NKT lymphocytes have been implicated in the regulation of autoimmune processes in both mice and humans. Activation of NKT lymphocytes leads to rapid amplification of either IFNγ or IL4, endowing these cells with the capability to mediate both pro-inflammatory and anti-inflammatory immune responses. Activation of this subset of cells is associated with significant liver damage in the Concanavalin A immune mediated hepatitis model. Administration of CD1d ligand has a protective role in collagen-induced arthritis in mice. Disease amelioration was associated with a shift in the immune balance from a pathological Th1 type response towards a protective Th2 type response. In humans, patients with SLE, scleroderma, diabetes, multiple sclerosis, and rheumatoid arthritis have lower numbers of peripheral NKT cells. NKT lymphocytes promote tumor rejection in experimental models of tumor immunotherapy. In contrast, NKT lymphocyterelated anti-tumor activity is associated with pro-inflammatory Th1-type immune responses. NKT cells were shown to have a role in suppression of hepatocellular carcinoma (HCC) via immune regulation towards tumor derived antigens, and adoptive transfer of dendritic cells pulsed ex vivo with the same antigens. NKT lymphocytes are activated by interaction of their TCR with glycolipids presented by CD1d, a nonpolymorphic, MHC class I-like molecule expressed by antigen presenting cells, and also by hepatocytes. Several possible ligands for NKT cells have recently been suggested including CD1d bound Glucocerebroside. Glucocerebroside (GC, β- glucosylceramide), a naturally occurring glycolipid, is a metabolic intermediate in the anabolic and catabolic pathways of complex glycosphingolipids. Its synthesis from ceramide is catalyzed by the enzyme glucosylceramide synthase. Inherited deficiency of glucocerebrosidase, a lysosomal hydrolase, results in Gaucher's disease. Patients with Gaucher's disease have altered humoral and cellular immune profiles and increased peripheral blood NKT lymphocytes. CD1d-bound glucocerebroside does not activate NKT cells directly, and may inhibit activation of NKT cells by α-GalCer. On the other hand, glucosylceramide-synthase deficiency was shown to lead to defective ligand presentation by CD1d, with secondary inhibition of NKT cell activation. Recent studies have suggested that a number of glycolipids, including GC, have an immune modulatory effect in several immune mediated disorders. The ability to alter NKT lymphocyte function in various settings and the potential application of natural glycolipids for treatment are discussed.

The transforming growth factor-β (TGF-β) superfamily includes TGF-β s, activin, myostatin and bone morphogenetic proteins. Misregulation of the activity of TGF-β family members is involved in pathogenesis of cancer, muscular dystrophy, obesity and bone and tooth remodeling. Natural inhibitors for the TGF-β superfamily regulate fine-tuning of activity of TGF-β family in vivo. In addition to natural inhibitors for the TGF-βfamily, soluble forms of receptors for the TGF-β family, blocking monoclonal antibodies and small chemical TGF-β inhibitors have been developed. In this review, we summarize recent advances in our understanding of inhibitors for the TGF-β superfamily and their medical applications.

Chronic infection with hepatitis C virus (HCV) remains a global health concern. Using both in vitro and cellbased assays, a series of small molecule agents specific for the viral RNA-dependent RNA polymerase have been shown to interfere with viral RNA replication. Although no agents targeting this viral enzyme have demonstrated sustained efficacy in infected patients as measured by reduction in viral load at 72 weeks post-treatment, proof-of-concept has been achieved in the clinic. A comprehensive account of the structure-activity relationship for nucleoside and non-nucleoside inhibitors of HCV polymerase, as well as consideration of early discovery biologic approaches targeting NS5B are reviewed.

Nowadays, drug discovery based on a single-target-directed strategy seems inappropriate for the treatment of complex diseases that have multiple pathogenic factors. Recent research into new drugs, which are able to hit different targets, highlights the idea that a single molecule could be sufficient to treat multi-factorial diseases. In this review, examples of multi-target-directed compounds derived from lipoic acid are examined.

The pipeline for new antibacterials is bleak despite the fact that infectious diseases account for a quarter of all worldwide deaths due to disease. Bacteria are ideal organisms for a systems biology approach to understanding pathogenesis by combined use of genomic technologies and computer algorithms. This approach can be applied to identify control points in molecular networks, which could be targets for novel drugs.