Current Topics in Medicinal Chemistry - Volume 8, Issue 7, 2008

Pathogenic microbial agents continue to cause a large number of infections and deaths. Their effects are particularly strong in people with a compromised immune system such as such as HIV or long-term hospitalized patients. Although effective chemotherapeutic agents are available for these individuals, the battle against infectious diseases is far from being over. The emergence and spread of antimicrobial resistance leads to the alarming conclusion that anti-infectious therapies are loosing their effectiveness. Resistance to first-line drugs, such as malaria or tuberculosis, has already been observed. Besides drug resistance can be considered as a natural response to drugs, their abuse and a poor patient compliance increase this public health problem. It is therefore necessary to discover new, safe and efficient agents against infectious diseases. This issue of Current Topics in Medicinal Chemistry addresses the most recent advances in anti-infectious agents against diverse important infections. First, Ronn and Sandstrom summarize the most recent achievements in the discovery of agents to treat Hepatitis C virus, which is recognized as the major cause of end-stage liver disease as well as the leading cause of liver transplantations in developing countries. The review is focused on small molecule antiviral drugs that target the structural components of the virus. Next, Pradines and co-workers report a new therapeutic strategy for the treatment of the most lethal parasitic disease, malaria. This new strategy, consisting in the use of compounds that have no intrinsic antimalarial effect in combination with extensively used antimalarial agents, proved to be a good solution to overcome resistance and also an excellent tool to elucidate the plasmodium falciparum resistance mechanisms. The third review by Pedrosa and co-workers describe the most recent advances in drug delivery systems of antimycobacterial agents for the treatment of mycobacterioses, focusing on two important pathogenic bacteria, mycobacterium tuberculosis, the causative agent of tuberculosis and mycobacterium avium which is responsible for a large percentage of nontuberculous mycobacterial diseases. The review describes that the association of antimycobacterial agents to liposomes or nanoparticles allows a more successful control of the disease. The next review, reported by Ting and Walker, is focus on the recently approved two new triazoles and an entirely new family of antifungal agents, the echinocandins, which have a new mechanism of action. They also discuss the use of other antifungal drugs under clinical evaluation and in the discovery phase. Finally, Cunnington and Nadel describe the current stage of a common clinical problem, the sepsis. The review summarizes the most recent advances in severe sepsis therapies and brings some perspectives to this important infection.

Hepatitis C virus (HCV) has deceived researchers for seventeen years now and although the current therapy regimen has been optimized by the development of pegylated interferon-α and the addition of ribavirin, no new agent to treat HCV infected patients has yet reached the market. A new era is approaching the HCV research due to new developments for the propagation of the virus in a cell-based system, which may lead to new drug innovations. Efforts in the search of new treatments for HCV infected patients are either focused on direct antiviral drugs, targeting the structural components or enzymes encoded by the virus, or indirect antiviral drugs, targeting host cell components (immunomodulators etc.). An inspection of the drug pipeline for HCV reveals representatives from both classes and of different mechanisms of action. Among the direct acting antiviral agents, inhibitors of the NS3 protease, the NS5B polymerase, and the viral RNA are the most intensively explored. However, there is also on-going and promising preclinical research, in different stages, on other potential targets as the structural protein E2 (for cell-entry inhibitors), the NS3 helicase, the p7 ion-channel, and the multifunctional NS5A protein. The combat of HCV will certainly require a combination of drugs of different mechanisms in order to reduce the emergence of resistance. The latest developments in the discovery of agents to treat HCV are reviewed, with special focus on direct small-molecule antiviral drugs, from a medicinal chemistry perspective.

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.e. chloroquine, quinine or mefloquine), have led to the emergence of drug resistance. Chloroquine and probably other quinolines act in interfering in the detoxification of hematin in the digestive vacuole. Quinolines are accumulated in P. falciparum digestive vacuole and the accumulation varies from a susceptible strain to a resistant one. Nevertheless, the mechanisms of quinoline resistance are still investigating. Genetic polymorphisms in some strains have been linked to drug resistance. The modifications observed are mutations on genes that encode transport proteins localized in the membrane of digestive vacuole. Three transporters were involved in quinoline resistance: PfCRT (Plasmodium falciparum chloroquine resistance transporter), Pgh1 (P-glycoprotein homologue 1) and PfMRP (Plasmodium falciparum multidrug resistance protein). They could be involved in accumulation or efflux mechanisms of drugs. In order to understand their role in resistance, localization, encoding gene structure, protein structure and endogenous function of these three transporters are reported. Some molecules that have no intrinsic antimalarial effect have been shown to reverse drug resistance when they are combined to chloroquine, quinine or mefloquine. These molecules are a solution to counter resistance but also they are precious tools to elucidate the resistance mechanisms. The molecules that have already shown a capacity to reverse chloroquine, quinine or mefloquine resistances were reported. Some of them could act on one of the three transporters involved in drug resistance, by confirming their role in quinoline resistance. Here we summarize the main elements of quinoline resistance and reversion of quinoline resistance related to malaria.

The clinical management of tuberculosis and other mycobacterial diseases with antimycobacterial chemotherapy remains a difficult task. The classical treatment protocols are long-lasting; the drugs reach mycobacteriainfected macrophages in low amounts and/or do not persist long enough to develop the desired antimycobacterial effect; and the available agents induce severe toxic effects. Nanotechnology has provided a huge improvement to pharmacology through the designing of drug delivery systems able to target phagocytic cells infected by intracellular pathogens, such as mycobacteria. Liposomes and nanoparticles of polymeric nature represent two of the most efficient drug carrier systems that after in vivo administration are endocytosed by phagocytic cells and then release the carried agents into these cells. This article reviews the relevant publications describing the effectiveness of the association of antimycobacterial agents with liposomes or nanoparticles for the treatment of mycobacterioses, particularly for Mycobacterium tuberculosis and M. avium infections. The increased therapeutic index of antimycobacterial drugs; the reduction of dosing frequency; and the improvement of solubility of hydrophobic agents, allowing the administration of higher doses, have been demonstrated in experimental infections. These advantages may lead to new therapeutic protocols that will improve patient compliance and, consequently, lead to a more successful control of mycobacterial infections. The potential therapeutic advantages resulting from the use of non-invasive administration routes for nanoparticulate systems are also discussed.

Fungi can cause life threatening diseases, particularly in patients with weakened immune systems. While treatment options are available for these individuals, dose limiting toxicity and the appearance of drug resistant organisms are growing problems. Therefore, the identification, development, and registration of new, safe, and efficacious agents are needed. Herein, we review recent developments in the field of antifungal drug discovery. We focus on recently launched drugs (triazoles and echinocandins), agents in clinical development, and compounds in discovery.

Sepsis is a common clinical problem that is responsible for an increasing number of deaths. Many new therapies for severe sepsis have been developed but few have shown benefit in rigorous clinical trials. To date the most successful therapies are relatively simple clinical interventions: appropriate broad spectrum antibiotics; early goal directed therapies to restore tissue oxygen delivery; physiological dose hydrocortisone in patients with relative adrenal insufficiency; intensive insulin therapy to maintain normoglycemia; and lung-protective ventilation strategies. The only adjunctive therapy supported by strong evidence of benefit is Activated Protein C. Experimental therapies are being developed with improved in vitro and animal models and better understanding of the pathophysiology of sepsis in humans. Neutralization of the triggers of inflammation, such as endotoxin, and inhibition of the signal transduction mechanisms are promising new strategies. Statins may be beneficial in prevention of sepsis and as adjunctive treatments. Reconstitution of the immune response with interferon-gamma or granulocyte-macrophage colony stimulating factor may reverse immunoparesis in severe sepsis. Many other molecular targets have been identified for possible therapeutic intervention, but there are still fundamental difficulties to be overcome in demonstrating efficacy in clinical trials.

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