Abstracts


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Promising Drugs Against Tuberculosis
Marcus V. N. de Souza

Tuberculosis (TB) is an important public health problem worldwilde due to AIDS epidemic, the advent of multidrug resistant strains (MDR) and the lack of new drugs in the market. TB is responsible for almost 3 millions deaths each year. According to WHO (World Health Organization), which declared tuberculosis a global health emergency in 1993, tuberculosis, without a coordinated control effort, will infect an estimated 1 billion people by 2020, killing 70 million. In spite of this problem, there is a lack of development of new TB drugs. For example, it has been nearly 35 years since the introduction of a new class of compounds for the treatment of TB. Thus, there is an urgent need for new drugs to fight against this disease. Considering that, this review aims promising drug candidates that are in development against TB.

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Patented HIV-1 Integrase Inhibitors (1998-2005)
Philippe Cotelle

Combination therapy, comprising at least three anti-human immunodeficiency virus (anti-HIV) drugs, has become the standard treatment of AIDS. Since 1996, highly active antiretroviral therapy (HAART) was designed to rapidly control HIV replication. It has had a significant impact on patient health and progression of AIDS in developed countries but its success has not been complete. HAART strategy still suffers from issues of patient compliance, cost, deleterious side effects and emerging drug resistance. Therefore it is logical to look for agents that inhibit different viral targets. In addition to the fusion, reverse transcription and protein formation processes, the HIV replicative cycle offers various other events that can be considered as potential targets for chemotherapeutic intervention. Amongst them integration is a key step and integrase (IN), one of the three viral enzymes, has been rapidly identified as a rational target for many years. To date, four molecules have entered in clinical trials. The present article reviews the increasing number of patents on small molecule HIV-1 integrase inhibitors in the 1998-2005 period, from the pioneer ones (discovery of selective strand transfer inhibitors) to the last patents including the actual molecules under clinical trials.

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An Insight on Targets and Patented Drugs for Chemotherapy of Chagas Disease
Vilma G. Duschak and Alicia S. Couto

Chagas disease or American Trypanosomiasis, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benznidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects and low efficacy. Therefore, there is an urgent need for new drugs to treat this neglected disease. Over the last two decades, new advances and understanding in the biology and the biochemistry of Trypanosoma cruzi has allowed the identification of multiple targets for Chagas disease chemotherapy. This review summarizes antichagasic agents obtained based on i) target metabolic biochemical pathways or parasite specific enzymes, ii) natural products and its derivatives, iii) design and synthesis of lead compounds. Related patents filed and issued from 2000 to early 2006 are also discussed. Most of them claimed inhibitors on specific parasite targets such as cysteine proteinase, sterol biosynthesis, protein farnesyltransferase, etc. Particularly, those related to cysteine proteinase inhibitors were the most represented. Natural products also displayed many anti-T cruzi lead compounds. In addition, a few patents claiming natural or synthetic compounds with antichagasic activity, disclosed no specific target. However, only a small proportion of all these patents displayed specific data of biological trypanocidal activity.

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Anti-Infective Quinone Derivatives of Recent Patents
Junko Koyama

Quinones are important naturally occurring pigments widely distributed in nature and are well known to demonstrate various physiological activities as antimicrobial and anticancer compounds. This review will focus on the preparation, therapeutic application, and administration of several benzoquinones, naphthoquinones, and anthraquinones having anti-infective, e.g. antiviral and antibacterial activities, in recent patents.

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NS5A - From Obscurity to New Target for HCV Therapy
Uli Schmitz and Seng-Lai Tan

The hepatitis C virus (HCV) non-structural 5A (NS5A) protein is essential for viral RNA replication and may play a role in subverting host intracellular signaling pathways. Although no intrinsic enzymatic activity has been ascribed to NS5A, this proline-rich hydrophilic phosphoprotein is likely to exert its functions by interacting with viral and cellular factors. Recent studies using the HCV replicon cell culture system as a model for HCV RNA replication as well as for high-throughput screening of pharmacological inhibitors have revealed blockade of NS5A as a promising therapeutic strategy for the treatment of HCV. This review will summarize our progress in understanding the role of NS5A in HCV RNA replication and will introduce the most recent patents on inhibitors of NS5A.

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Probiotics as Drugs Against Human Gastrointestinal Infections
Yolanda Sanz, Inmaculada Nadal and Ester Sanchez

The commensal gut microbiota confer health benefits to their host by helping dietary digestion, regulating gut immunity, maintaining the microbial balance, and preventing pathogen colonization. A number of probiotic strains have been introduced in the market in dietary and pharmaceutical forms. Lactic acid bacteria (e.g. Lactobacillus) and Bifidobacterium constitute the main group of probiotics commercialized for human consumption. The treatment of gastrointestinal infections continues to be complicated due to the expansion of antibiotic resistances. Of the benefits of probiotics, those related to their preventive and therapeutic uses against gastrointestinal infections have an outstanding position, as reflected in a large number of patents. The mechanisms of action of probiotics against gastrointestinal pathogens addressed in diverse patent applications include: (i) modification of the environmental conditions, (ii) competition for nutrients and adhesion sites, (iii) production of antimicrobial metabolites and (iv) modulation of the immune and nonimmune defense mechanisms of the host. The bioactive components of probiotics include cell-wall fractions, surface proteins, nucleic acids, organic and short-chain fatty acids, antimicrobial proteins and other less-well identified soluble factors. The effectiveness of probiotics is supported by solid clinical studies mainly on treatment of acute diarrhea in children and prevention of antibiotic associated disorders. Currently, probiotics and their bioactive compounds constitute attractive alternative drugs that can help to reduce the use of antibiotics as well as to improve conventional pharmacological therapies. The advances on the knowledge of the intricate host-microbe dialogues within the intestine and extraintestinal sites will result in the future development of a new generation probiotic-based products targeting broader range of pathologies and their etiologic agents.

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Registered and Investigational Drugs for the Treatment of Methicillin-Resistant Staphylococcus aureus Infection
Angelo Pan, Silvia Lorenzotti and Alessia Zoncada

First isolated in the 1960s methicillin-resistant Staphylococcus aureus (MRSA) has become a leading hospital acquired (HA) pathogen, although community acquired isolates (CA-MRSA) are on the rise, particularly in the USA. Treatment of serious MRSA infections has been based for many years upon the use of glycopeptides, i.e. vancomycin and teicoplanin. Other drugs indicated in particular clinical settings, such as prosthetic valve endocarditis or osteomyelitis, are rifampin, gentamycin, fusidic acid, minocycline, co-trimoxazole, clindamycin. Quinolones and doxycycline may be active on some MRSA isolates, and add some this important clinical setting. In the last few years new anti-MRSA drugs have been registered and patented, expanding therapeutic opportunities, i.e. linezolid, the first oxazolidinone, available both as oral and parenteral formulation in being the most widely used new anti-MRSA agent, quinupristin-dalfopristin, daptomycin, a novel lipopeptide, active on germs both in the replicating and in the resting phase, and tigecycline, the first approved glycylcycline. Other drugs from different classes are in the pipeline and will further enhance in the next few years our therapeutic armamentarium: three glycopeptides, i.e. dalbavancin, telavancin, and oritavancin, two broad spectrum cephalosporins, ceftobiprole and ceftaroline, iclaprim, a diaminopyrimidine, as well as a carbapenem, CS- 023/RO-4908463, and adjuvant therapies such as the monoclonal antibody tefibazumab.

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Current Status and Future of Antifungal Therapy for Systemic Mycoses
Joshua D. Nosanchuk

Since the 1950s there has been an increase in the incidence of invasive fungal disease. The first successful systemically administered antifungal drug, amphotericin B, was introduced in the 1950s and, until very recently, was considered the best therapeutic drug for severe mycoses. The development of new antifungals to treat systemic disease has been slow compared to that of antibacterial compounds, with the introduction of only a single new class of drugs over the past 20 years. This review discusses the antifungal drugs that are clinically in use and summarizes interesting new applications and patents from the US Patent and Trademark Office.