Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 6, Issue 3, 2007

Nearly 3 decades ago, a dendritic structure was stepwise synthesized for the first time as a new type of molecules with promising applications. During years a huge effort has been devoted to implement the synthetic skills concerning the synthesis of these molecules and especially, new methods for purification and characterization of these compounds that are in the nanoscale range. The chemical manipulation of the surface and inner core of dendrimers were strategically used to allow a tailor-made control of physical-chemical properties and to discover new applications in material science and biomedicine. Although several examples have been reported in the literature describing applications of functionalized dendrimers and acclaiming a key role of these molecules, very scarce examples are actually close to the market. This review summarizes the state of the art of dendrimers and dendritic polymers as anti-infective agents, with a special focus on the strategies to block receptors used by pathogens for attachment, cell entry and dissemination. These nanometre size molecules are very attractive compounds as new drugs easily to be manipulated to improve their activity and scope. This is already a very active area of research, where we are involved, with interesting potential as demonstrated by the Phase I clinical trial of a functionalized dendrimer with real possibilities to reach the market soon. The success of this compound should provoke an enormous stimulus to scientists working in this area as well as in the industrial companies for investment in this topic.

The increasing number of antibiotic resistant bacterial strains presents an emerging world health problem that demands continued effort to develop new antibacterial compounds. Endogenous antibacterial peptides (ABPs) that are constitutively and/or inducibly produced in tissues exposed to external surroundings represent new candidates for development of such compounds. Most ABPs target bacterial membranes initially by electrostatic interactions between positively charged amino acids and negatively charged molecules present on bacterial walls, followed by compromise of the permeability barrier of bacterial membranes through the formation of pores, leading to rapid cell death and efficient bacterial elimination. Other mechanisms, such as the inhibition of bacterial protein and DNA synthesis or receptor-mediated stimulation of host defense mechanisms are also ascribed to these molecules. The activities of ABPs correlate positively with a gradient of hydrophobicity along the peptide backbone, net positive charge at neutral pH, and secondary structure. More than 850 sequences with antibacterial activity have been described, and this number continues to grow with the addition of newly discovered, as well as synthetic, peptides. Many strategies, including increasing net positive charge, increasing net hydrophobicity, conjugation of peptides with lipophilic acids, incorporation of carbonate bonds, and synthesis of their hybrids and truncated sequences that omit hemolytic regions, have been proposed to increase efficiency of synthetic ABPs. Additionally peptide-mimicking molecules such as cationic steroid antibiotics (CSAs) may be useful alternatives to natural ABPs. Current challenges for practical application of ABPs are the high cost of synthesis/isolation, inactivation by blood plasma, confinement by anionic polyelectrolytes, and possible unknown toxicity.

Despite the availability of antibiotics, infectious diseases become an even increasing threatening for human health, in particular due to resistance development, for example in animal husbandry. Furthermore, the sepsis shock syndrome, which in many cases is a result of the fact that antibiotics may kill bacteria, but do not inactivate bacterial virulence factors such as endotoxins (lipopolysaccharides), is worldwide of increasing importance regarding the very high death rate (40 to 50 %). Therefore, the development of suitable antimicrobial drugs is urgently requested. In recent years, various groups focus on the use of antimicrobial peptides (AMP) derived from natural, innate immunity proteins, which in vivo bind to the virulence factors. Such binding proteins are, for example, lactoferrin, the Limulus anti-LPS-factor, and the family of saposin-like proteins (NK-lysins, granulysins), which all have particular binding domains for example for bacterial endotoxin. Furthermore, an alternative approach to combat infections is the use of cyclooxygenase and lipoxygenase inhibitors. From the reviewed literature the mechanisms of action of antiinfective compounds on bacteria, on pathogenicity factors of the bacteria, and on viruses are summarized. In the last years, considerable progresses have been made in the fight against infections, specially also to overcome bacterial resistance.

The echinocandins are a new class of antifungal lipopeptides for the treatment of serious nosocomial mycoses. The three currently approved drugs, caspofungin, micafungin, and anidulafungin, were each discovered through the synthetic modification of echinocandin natural products obtained from fermentation. This review is intended for the medicinal chemist who is actively pursuing or has a general interest in the synthetic modification of natural products as a means to identify drug candidates. It provides a survey of the synthetic strategies that produced the approved echinocandin therapeutics and a discussion of more recent efforts to identify a new generation of echinocandin drug candidates. Both total synthetic approaches starting from the constituent amino acids and semi-synthetic approaches relying on fermentationproduced lipopeptide are addressed. These various efforts by chemists from industry and academia have not only illuminated the interesting chemistry of these natural products, but have provided the means by which improvements in antifungal potency and spectrum, pharmacokinetic profile, solubility, stability, and safety can be realized. The ultimate success of these efforts can be judged by considering the important role the echinocandins are already playing in the treatment of serious fungal infection.

Since the mid-1980s, the nucleoside reverse transcriptase inhibitors (NRTIs) have established their position as valuable antiretroviral (ARV) agents in the treatment of human immunodeficiency virus (HIV) infection. Today, NRTIs still constitute the “backbone” of highly active ARV therapy regimens. The combination of different ARV classes has enabled the goal of successful suppression of HIV replication to be achieved in most HIV infected patients and is currently standard of care to prevent the development of AIDS. The NRTIs and nucleotide reverse transcriptase inhibitors (NtRTIs) are prodrugs which require intracellular phosphorylation before they become active compounds. Apart from zidovudine they are all water soluble, and generally have a wide volume of distribution. The NRTIs undergo a three step phosphorylation process whilst the one currently available NtRTI, tenofovir, only requires two phosphorylation steps to create a clinically active diphosphate metabolite. The active phosphorylated derivatives then compete with the endogenous nucleotides for viral reverse transcriptase. Several steps in intracellular phosphorylation are rate limiting and a number of intracellular factors can affect this metabolism. There are also external influences which can affect this process. The intracellular factors include: cell type; timing within the cell cycle; levels of dideoxynucleoside analogue triphosphates (ddNTPs) created by the phosphorylation of NRTIs, and endogenous cellular deoxynucleotide triphosphates (dNTPs) which compete for substrate binding to reverse transcriptase. Importantly, drug-drug interactions involving NRTIs with other ARVs as well as with non-HIV classes of drugs are complex and may lead to the development of toxicity or limit drug efficacy. This is of particular importance with the numerous new agents in development The review will discuss the main pharmacological characteristics of the available and investigational NRTI/NtRTIs and a brief summary of the possible drug interactions which may occur between different ARV agents. An extensive discussion of drug-drug interactions between ARVs and other agents is outside the scope of this review.