Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 7, Issue 4, 2008

In the search for effective, selective and nontoxic antiviral agents, a variety of nucleoside analogues have been synthesized, with different functionalities in the carbohydrate moiety. Unsaturated nucleoside analogues are recognized as an important class of biologically active compounds and appear to be prominent drugs in the management of several viral infections, including HSV, HIV, HBV, HCV and HCMV infections. Currently, unsaturated nucleoside mimetics, such as stavudine, abacavir and entecavir have been approved for the treatment of viral infections, while elvucitabine and β-L-2β- F-d4C are in clinical trials. The purpose of this review is to give an update of the recent developments on unsaturated nucleoside and nucleoside analogues, in both cyclic and acyclic forms, which possess promising therapeutic potential, mainly antiviral. It covers analogues with ring sizes from three to six and provides useful data, in the aim to enhance chemical reactivity or to study the fixation of the sugar conformation.

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15%-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. Approved drugs for chronic hepatitis B treatment include: standard interferon-alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. Unfortunately, these agents are not effective in all patients and are associated with distinct side effects. Interferons have numerous side effects and nucleoside or nucleotide analogues, which are well tolerated, need to be used for prolonged periods, even indefinitely. Telbivudine is a novel, orally administered nucleoside analogue for use in the treatment of chronic hepatitis B and it was approved by the FDA in late 2006. In contrast to other nucleoside analogues, Telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine has demonstrated potent activity against hepatitis B with a significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment, and adefovir. Telbivudine has been generally well tolerated, with a low adverse effect profile, and at its effective dose, no dose-limiting toxicity has been observed. The aim of this review is to evidence the pharmacodynamic and pharmacokinetic characteristics of this drug and to evaluate its efficacy and tolerance.

The treatment of infectious diseases has been complicated by the rising of new pathogens, the spread of antibiotic- resistant strains and the relative inefficacy of antimicrobial chemotherapy in immunocompromised hosts. This has led to renewed interest in the utilization of antibody-based therapies as anti-infective agents. Antibody-based therapies are effective against a wide variety of pathogens. In recent years they have become first-line therapy for a variety of conditions that include viral infections, inflammatory disorders, and certain malignancies. Renewed interest in antibody-based therapies is a consequence of major advances in antibody production technology and the need for new therapeutic agents. Dozens of antibody preparations are in clinical use. Several monoclonal antibodies (mAb) are now licensed for clinical use and many are in advanced clinical development. As a class, antibody-based therapies have significant advantages and disadvantages when compared to conventional antimicrobial chemotherapy. Advantages include versatility, specificity, and antimicrobial activities not available in antibiotic drugs, such as toxin and viral neutralization, opsonisation, complement activation and the enhancement of host immune function. Disadvantages include expense, the necessity for early and accurate diagnosis prior to use, and the complex logistics necessary for therapeutic use. Advances in antibody technology have minimized some of the disadvantages associated with antibody therapy. The recent spread of hybridoma technology among laboratories has promoted the development of mAb use against a wide variety of infectious disease agents. Monoclonal antibodies have in fact been used to identify new antigenic determinants in various microorganisms, to show antigenic differences between species, strains, types and development cycles and to reveal the existence of natural antigenic variants. While mAb theoretically represent an excellent (perhaps superior) alternative to conventional antisera as diagnostic, therapeutic or laboratory reagents, traditional antisera may be preferable to mAb in some circumstances because of its fixed affinity and specificity as well as the limited functional capacities of some antibodies. The acceptance of mAb by the clinical microbiologist and physician must await proof of their reliability, safety and efficacy. Continued success in the development of antibody-based therapies will require extensive clinical research to learn how to use these compounds optimally and immunological research to define the basic mechanisms of antibody action. Given the need for new antimicrobial therapies and many recent technological advances in the field of immunoglobulin research, there is considerable optimism regarding renewed applications of antibody-based therapy for the prevention and treatment of infectious diseases. In this paper, we review the applications of immune therapy for infectious diseases.

The Oxazolidinones are a promising novel chemical synthetic class of antibiotics identified in the last two decades and have been subjected to intensive discovery efforts. They possess impressive antibacterial activity against Grampositive pathogens. Oxazolidinones act through a unique mechanism of inhibitory bacterial protein biosynthesis. Linezolid (ZyvoxTM) has been the only drug of oxazolidinone class to reach the market after USFDA approval. Here we review our efforts directed to the discovery of novel oxazolidinone antibacterials evolved through structure-activity relationship (SAR) and an overview of contemporary on going efforts.

The aim of this study was to investigate the efficacy different of throat antiseptics on the oropharynx in healthy volunteers. A newly developed standardised test method was established. Using 12 volunteers per product to be tested, the reduction in the total colony count was the primary endpoint, and reduction in viridans Streptococci was the secondary endpoint criterion, for the commercial antiseptics neo-angin® N throat lozenges, neo-angin® N sugar-free lozenges, neoangin ® N throat and mouth spray, Sorot® lozenges, and Hexoral® mouth wash. At baseline, immediately, 2 and 5 hours after application two areas of the oral mucosa in the lower jaw at the level of the second molars and from the uvular region were swabbed and investigated for total bacterial counts. Following neutralisation, the swabs were inoculated onto blood agar. The antiseptic effect was more prominent in the throat, the area targeted by the antiseptic, than in the cheek mucosa. The reduction in total colony count was significant both with the test preparations and with the comparison preparations; A reduction of > 1 log was achieved for both endpoint criteria immediately after application of antiseptic and continued at this level for 30 minutes. Even after 5 hours, a significant reduction in total colony count was observable. Furthermore the established test model allowed determining the antiseptic efficacy of lozenges or spraying preparations in comparison to rinsing solutions.

Tenofovir disoproxil fumarate (tenofovir DF) is the generic name of the chemical compound 9- [R- (2[[bis]]isopropoxycarbonyl) oxy]methoxy]phosphonyl]methoxy]propyl] adenine fumarate (1:1), the prodrug of tenofovir, the first nucleotide analogue reverse transcriptase inhibitor approved in October 2001 by the Food and Drugs Administration in USA and then, in February 2002, by the European Medicines Evaluation Agency in Europe for the treatment of HIV infection. In a short time it has become one of the most widely prescribed agents in HAART regimens both in naive and experienced patients, and is one of the most frequently used antiretroviral drug in ongoing clinical trials for the treatment but also for the prevention of HIV infection. Why has it gained a so important role in the management of HIV infection? This brief report emphasizes the key aspects of tenofovir, concerning its pharmacokinetic and pharmacodynamic properties, and its therapeutic efficacy and safety.