Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 5, Issue 1, 2006

The synthetic class of azole antimycotics constitutes the largest group of antifungal agents currently in clinical use. Widespread use of azoles has led to the rapid development of multiple drug resistance, which poses a major hurdle in antifungal therapy. The generally accepted mode of action of azoles is the inhibition of 14α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis, resulting in depletion of ergosterol and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast species. For some azoles, their antifungal mode of action is not only characterized by inhibition of ergosterol biosynthesis. Recently, it was shown that generation of reactive oxygen species (ROS) is important for the antifungal activity of miconazole, pointing to an ancillary mode of action for this azole. We further analysed the effect of other azole antifungals on ROS generation in Candida albicans and could demonstrate that only miconazole induces ROS production in C. albicans. Furthermore, we show that the miconazole induced ROS production is probably caused by inhibition of the enzymes implicated in breakdown of peroxide radicals and hydrogen peroxide, i.e. peroxidase and catalase. Interestingly, only miconazole was found to exert its antifungal effect in a fungicidal way. In conclusion, further development of novel azole antimycotics, based on the chemical structure of miconazole and on its related ROS inducing capacity/fungicidal activity would be an interesting approach to address the problem of resistance occurrence.

The aim of this review is to collect, systematize and contrast the many recent advances in xanthones' biochemistry and biology. Advances in understanding xanthones' antimicrobial activities will be discussed. Pharmacological and biological properties of naturally occurring as well as synthetic xanthones will be considered in an evaluation of their medical values.

Surfactants in general are well known for their ability of disrupting cell membranes and damaging microbes. However, cationic surfactants and lipids exhibit interesting additional properties because they can easily be targeted to oppositely charged biological structures such as cells or biomolecules of interest. This review emphasizes physicochemical and antimicrobial properties of cationic lipids and surfactants aiming at the establishment of structure-activity relationships. In special, cationic lipids forming bilayers revealed multiple abilities to carry antibiotics, drugs, genes, and antigens sometimes exhibiting synergic effects with the drug carried or displaying anti-infective properties by themselves.

The clinical field of rheumatology utilizes numerous medications which are either structurally derived from antibiotic compounds or are actually originally track - record proven anti - infective agents adapted for use in this field. Though in many cases, exemplified by rheumatoid arthritis, a presumed infectious etiology brought about the introduction of these drugs into rheumatology, subsequent research has often failed to demonstrate an infectious agent; nevertheless such originally anti - infectious agents as hydroxychloroquine and sulfasalazine have gained a place in the rheumatologic armamentarium. This sequence of events implies that in many cases anti - infective agents posses anti - inflammatory or immuno - modulatory qualities not directly linked to their potential capacity to kill foreign pathogens. More recently agents such as cyclosporine and tacrolimus, both of antibiotic structure, have been developed specifically for their immuno - modulatory effects. This review covers the main events in the development of anti - infective agents for rheumatology and attempts to clarify the often enigmatic relationship between these two seemingly unrelated fields.

Anti-malarial chemotherapy based on a limited number of drugs has been the mainstay of malaria control for many decades. However, the lack of new effective and affordable drugs and the emergence and spread of drug resistant parasites is seriously hindering treatment strategies, and is contributing to the resurgence of malaria, especially that caused by Plasmodium falciparum. Present knowledge indicates that drug resistance in malaria emerges through selection of parasites harbouring genetic mutations that confer a selective advantage over sensitive parasites in the presence of drug pressure. Resistance to antifolates such as Fansidar®, (pyrimethamine in combination with sulphadoxine), is known to be caused by mutations in the genes encoding the drug's therapeutic targets, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). In the case of quinoline-based compounds, such as chloroquine and mefloquine, resistance is thought to be dependent on the exclusion of the drug from the site of action. This has been shown to be mediated by mutations in two genes denoted pfmdr1 and pfcrt, which encode proteins localized on the membrane of the parasitophorous food vacuole where these drugs are thought to act. In recent years, heath authorities have been increasingly recommending the use of Artemisinin Combination Treatment (ACT) in an effort to halt the spread of antimalarial drug resistance. Resistance to artemisinin derivatives has not yet been reported in natural human parasite populations, but it has already been achieved in rodent malaria models suggesting it may arise also in P. falciparum. Major focus should now be aimed at understanding the mechanisms of resistance to artemisinin derivatives before it becomes a serious public health problem. The post-genomic era of malaria has opened unprecedented opportunities for a better understanding of drug resistance mechanisms and consequently, for rational design of novel compounds less prone to resistance.

Approximately 350-400 million people of the world are chronically infected with the hepatitis B virus, and it is these individuals that harbor the virus for their whole life and are responsible for its transmission to uninfected populations. Considerable numbers of chronic hepatitis B virus carriers develop progressive liver diseases like chronic hepatitis B, liver cirrhosis and hepatocellular carcinoma. Current treatments for chronic hepatitis B include interferon, and antiviral drugs such as lamivudine, adefovir, and entacavir. These antiviral treatments are not satisfactory in that they are unable to eradicate the hepatitis B virus, expensive, can have debilitating side effects, and, once treatment is stopped, the virus and clinical conditions return in many individuals. Recent advancements in various aspects of cellular and molecular biology indicate that the host's immune responses to the hepatitis B virus play cardinal role during acquisition, pathogenesis, progression and complications of chronic hepatitis B virus infection. These also explain the limitations of antiviral drugs for treatment of these patients. Here, we will first provide a comprehensive account of hepatitis B virus. Next, the scopes and limitations of present regimens of antiviral drugs in chronic HBV carriers will be provided. Finally, the rationale and strategy of immune therapies including dendritic cell-based therapies against chronic hepatitis B virus infection will be discussed.

Retinoids play a critical role in the regulation of cell division, growth, differentiation, and proliferation, and represent an exciting new avenue for targeted therapy of different diseases, including cancer. Natural and synthetic retinoids are also endowed with antiviral properties that make these compounds particularly attractive for the prevention and treatment of infection-driven tumors. In this review, we will summarize the structural bases and the cellular and antiviral effects of retinoids which provide a molecular basis for the management of virus-associated tumors, including Kaposi's sarcoma (HHV-8) and post-transplant lymphoproliferative disorders (EBV). Particular relevance will be given to the selectivity of these retinoids for their cognate receptors (RAR and RXR) in order to establish a link between receptor modulation and antiviral/antitumor effects.

Malaria with 1 million deaths and about 500 million new cases reported annually is a challenge to drug therapy and discovery. Drug resistance accompanied by lack of progress in the development of vaccines or resistant reversal agents has further aggravated the situation. In this scenario, development of antimalarials acting by novel pathways is the best option. Decoding of the Plasmodium falciparum genome has helped scientists working in the area of drug development by providing new drug targets such as carbonic anhydrase, homocysteine hydrolase, antioxidant proteins, glutathione reductase etc. Efforts are ongoing to elucidate structures and functions of novel targets. These developments will form an important part of this review. Developments related to novel antimalarials such as Ugi adducts of chloroquine, polar derivatives of artemisinins, amino acid complexes of 8-aminoquinolines, bioimidazoles, t-butylperoxyamines etc will also be reviewed. We are working on drug discovery leading to development of novel antimalarials. A basic nucleus pyrimido-[4,5- b]quinoline was developed based on pharmacophoric studies. Appropriate substitutions on this basic nucleus taking into consideration overall basicity and lipophilicity are the prime considerations in the development of novel antimalarials. Preliminary work led to synthesis, characterization and evaluation of nine novel derivatives for antimalarial activity in mice infected with P. berghei using chloroquine as standard. Five out of nine derivatives were active and among these, three derivatives were found to be more potent than chloroquine. Encouraged by this positive outcome, additional novel derivatives are being developed. Efforts are also on to establish the likely targets with which these novel molecules interact.