Current Medicinal Chemistry - Volume 16, Issue 20, 2009

Virus infection is one of the major threats to human health and can be avoided by minimizing exposure to infectious viruses. Viral clearance of pharmaceutical products and sanitization of skin and mucosal surfaces would reduce such exposures. Even with such care, virus infection does occur, requiring effective treatments by antiviral or virucidal agents. Natural products, in particular ingredients of foods and drinks we normally consume or metabolites present in human body at low concentrations, would have advantage over synthetic drugs as antiviral agents for safety concerns. For this reason, we have been studying natural products for their effects on virus inactivation and growth. Such natural products, which we have been focusing, include gallate derivatives, caffeine present in coffee, caffeic acid present in coffee and various fruits, ascorbic and dehydroascorbic acids and a cell metabolite, arginine. Here we will review our work on antiviral and virucidal activities of these compounds and the mechanism of their antiviral and virucidal effects.

Amyloid is a term used to describe protein deposits with circumscript physical characteristics: β-pleated sheet configuration, apple green birefringence under polarized light after Congo red staining, fibrillary structure and high insolubility. Cerebral amyloid angiopathy (CAA) defines a clinicopathological phenomenon characterized by amyloid deposition in the walls of leptomeningeal and cortical arteries, arterioles, and, less often capillaries and veins of the central nervous system. CAAs are currently classified according to the protein deposited including amyloid β peptide (Aβ), cystatin C (ACys C), prion protein (PrPSc), ABri/ADan, transthyretin (ATTR), and gelsolin (AGel). Most often amyloid deposition occurs in sporadic forms. In less common hereditary forms, a mutated variant protein or precursor protein is abnormally metabolized by proteolytic pathways in consequence of specific gene mutations, and accumulates as amyloid. The spectrum of clinical phenotypes associated with CAA-related vasculopathic changes includes both ischemic and hemorrhagic presentations, primary intracerebral hemorrhage (PICH) being probably the most well-recognized. However, in spite of accumulating data and recent progress in understanding the pathogenesis of CAA-related hemorrhage, the exact mechanisms leading to vessel rupture in these cases are yet to be established. This represents, at present, a major limitation to the identification of reliable biomarkers and the development of disease-specific treatment options. The present paper summarizes epidemiologic and clinical aspects of CAA, and highlights the presumed pathomechanisms of amyloid deposition in both sporadic and hereditary forms.

Pneumocystis remains an important cause of fatal pneumonia (PCP) in HIV patients and other immunocompromised hosts. Preclinical drug discovery for agents active against PCP has been hindered in large part by the lack of a continuous in vitro growth system. Since approval in 1978, the combination of the folic acid synthesis inhibitor combination trimethoprim-sulfamethoxazole has been the primary agent for prophylaxis and therapy. Short term in vitro assays using cell monolayer-based and cell free systems in combination with in vivo studies in rodent models of infection have been the mainstay of candidate screening methods. These systems and their applications are reviewed here. Most strategies have focused on testing compounds already in clinical use, such as dapsone or atovaquone, for activity against Pneumocystis alone or in combination, and as parent compounds for chemical derivation, such as pentamidine and its analogues. Other successes from the bench include primaquine-clindamycin for moderate pneumonia and the family of Betaglucan synthase inhibitors, which hold promise for clinical use against PCP. Despite the significant obstacles for drug discovery, progress in identifying novel agents has been made with current systems and the promise of future new targets is expected with the annotation of the Pneumocystis genome.

Combinatorial chemistry has become an important tool in the area of modern drug discovery and its success is partly dependent on further advances of solid phase organic synthesis (SPOS). Indoles are an important class of compounds with a broad spectrum of biological activities. Therefore, considerable attention is given for the development of effective methodology for the substituted indoles not only in solution phase but also on solid phase. In this review, indole forming classical reactions such as Fisher, Nenitzescu, Bartoli, Modified Madelung, Modified Bischler, and Wittig type reactions on solid support are summarized. In addition, metal mediated cyclizations such as palladium, and rhodium catalyzed cyclizations along with microwave-assisted solid phase synthesis of indoles have been discussed. Also, the most relevant biological properties of indoles have been reported.

DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides or the D-Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis. Their function is essential for bacterial growth and specific to bacteria, making them attractive targets for the development of novel antibiotics. This review examines the biochemical and structural features of these enzymes and presents the main families of inhibitors described so far. Over the last 20 years, 7 structures of DD-ligases have been solved by X-ray crystallography, giving a detailed view of the general topology of the active site and of the residues in the catalytic pocket that play a central role in substrate recognition. This has paved the way to the rational design of inhibitors, which can be classified as (i) analogues of substrates, (ii) analogues of the product of the reaction, (iii) analogues of the transition state, and (iv) original scaffolds discovered by screening or by rational computer-aided design. The three first strategies have led to molecules that are polar by nature and have therefore poor access to their cytosolic target. The fourth one is potentially most promising as it yields more diverse structures. The most active molecules show affinity constants in the μM range, but microbiological evaluation remains scarce (typical MIC 1-8 mg/L for the tested compounds). These data strongly suggest targeting DD-ligases is a promising approach for discovery of new antibiotics. Future research should, however, aim at finding more potent inhibitors endowed with the appropriate pharmacokinetic properties that ensure access to their intracellular target.

In this review, an updated literature survey covering the reports of naturally occurring xanthones in the period of 2005-2008 is presented. In some 143 studies, the isolation of 264 different xanthones from 36 plant species (representing 15 genera in 6 families of higher plants), 7 species of fungi, and 1 lichen species were reported. Of these, 122 compounds were isolated for the first time from nature. We discuss plant origin, the way of separation, and spectral analysis done for structure elucidation, along with a brief discussion of the chemosystematic significance.