Current Medicinal Chemistry - Anti-Infective Agents - Volume 3, Issue 2, 2004

Helicobacter pylori (H. pylori) infections are known to cause gastritis and peptic ulcers, and dramatically enhance the risk of gastric cancer. Today, eradication of this organism is an important medical goal. Recent efforts to discover potential candidates of anti-H. pylori agents have been devoted to screen plants which are used in traditional medicine. Potent anti-H. pylori compounds are identified through both the initial screening of pure natural product derived compounds and those derived from bioassay-guided fractionation of crude natural product extracts. It is suggested that several plants and their principles may be effective agents for the treatment of symptomatic and asymptomatic forms of H. pylori infections. The purpose of this paper is to review recent literatures of anti-H. pylori agents from natural products (until March 2003).

Macrolide antibiotics are noted for their intracellular accumulation and activity against intracellular pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. Apart from antimicrobial activities, macrolides can modify host cell functions. Indeed, several in vitro- and ex vivo-studies have shown that macrolides influence polymorphonuclear cell functions as well as cytokine production by several cell types. In this way macrolides may change host immune responses, and thus may be used as immunomodulating agents. Immunomodulation (i.e., therapy that modulates the immune response of the host) may serve as an important adjuvant to antibiotic therapy in the treatment of infectious diseases or infection-related illnesses in several ways: therapy may be aimed at upregulation of the inflammatory response in case the host response is too “weak”. Conversely, downregulation of inflammatory responses may protect the host against the deleterious consequences of immune hyper-activation, when the host response is too “vigorous”, or when the host response is too persistent. The scope of this manuscript is to describe the effects of macrolides on innate immunity in the pulmonary compartment (i.e., the innate host defense during pulmonary infections and pulmonary (non-infectious) inflammation). We will first describe the various in vitro- and ex vivo-effects of macrolides; thereafter, we will give an overview of animal studies on non-antimicrobial activities of macrolides. Finally, usage of macrolides in panbronchiolitis and cystic fibrosis is highlighted. The approach of using antibiotics (e.g., macrolides) as immunomodulating agents, however, carries the risk of (respiratory tract) colonisation and possible clinical infection with antibiotic-resistance organisms.

Highly active antiretroviral therapy (HAART) has dramatically decreased the morbidity and mortality related with HIV-1 infection. However, at the same time, the impossibility of eradicating the infection has made lifelong therapy with antiretrovirals necessary. This has caused the emergence of multiple side effects, including previously unseen and unexpected adverse drug reactions. In addition, the combination of different classes of drugs sometimes sharing common toxic mechanisms has made additive toxicity an increasing event. The purpose of the present work is to review the molecular mechanisms of action of the different antiretrovirals now used in clinical practice, and through these to gain insight into the potential mechanisms of antiretroviral drugsassociated toxicity. Two basic mechanisms of toxicity have been described associated with antiretroviral drugs; i.e. mitochondrial toxicity associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs), and the metabolic toxicities associated with HIV-1 protease inhibitors. Both types of mechanisms eventually cause multiple clinical manifestations, and among them, the most important are the fat redistribution syndromes associated with HIV-1 infection and HAART. On the other hand, the growing knowledge about the pathogenic mechanisms of antiretroviral drugs-associated toxicities has promoted advances in the therapeutic approach, and overall, the design of new and promising antiretroviral drugs that may avoid some of the prior deleterious consequences of antiretroviral drug administration. In the context of long-term antiretroviral treatment for longterm surviving HIV-1 infected patients, this may be the best hope for the still growing number of infected patients worldwide.

Malaria remains the first world-wide parasitic disease with an estimated 2.7 million deaths per year, most of them occurring in Africa. The parasite, Plasmodium falciparum, has demonstrated its extreme skill at adapting to all drugs currently in use (like chloroquine (CQ)) and resistance to these drugs has spread almost all over the world. Therefore (multi)drug resistance has become one of the most important problems. Whereas the discovery of an antimalarial compound with no possibility of resistance seems utopian, new strategies have been developed to overcome the situation. The most promising results come from the new area of bioorganometallic chemistry with the synthetic compound Ferroquine (FQ). In vitro, FQ inhibits at nanomolar concentrations the growth of chloroquino-resistant strains and isolates P. falciparum. Its schizontocidal activity was confirmed in murine models. Chemical modifications of FQ were attempted to correlate structure with activity. Some physicochemical properties of FQ were investigated to elucidate its mechanism of action. This strategy, based on incorporation of an organometallic moiety into the “standard” drug, offers new possibilities in reversal of resistance and therapeutic application. The review will conclude by presenting the present industrial development of FQ.

Involvement of sialidases in a variety of microbial infections apart from that by influenza virus has been demonstrated but in contrast to the latter, where potent inhibitors have been developed on the basis of the lead compound 2-deoxy-2,3-didehydro-N-acetylneuraminic acid, inhibitor design for bacterial or trypanosomal sialidases has proven to be much less straightforward. This review intends to give an overview of the attempts, which have been made, including both substrate analogues and transition-state analogues of the sialidase reaction as well as structurally unrelated compounds. The bifunctionality of the viral haemagglutininneuraminidases, supported by recently obtained crystal structure data, or the modular architecture of some bacterial enzymes provide useful starting points for improvement of inhibitors through additional interactions beyond the active site itself. This seems especially to be the case for trypanosomal trans-sialidases the inhibition of which might require some sort of acceptor mimic in addition to the sialic acid analogue.

Since the discovery of brassinolide, a C28 steroid with an unusual lactone B-ring structure, more than 60 related compounds -collectively known as brassinosteroids (BRs) - have been isolated from a wide variety of plant species. Exogenous application of BRs to plants at nanomolar to micromolar concentrations has a broad spectrum of growth responses, such as stem elongation, inhibition of root growth, promotion of cell division and enhancement of stress resistance, brought about by changes in enzyme activity and gene expression. In the last years, biochemical and genetic analysis provided compelling evidence for an essential role of BRs in plant development. In this paper, we review our synthetic methods to obtain BRs analogues and report the scope of antiviral activity of these compounds against RNA and DNA viruses. Some of the compounds showed selectivity indexes (SI) 10- to 18- fold higher than ribavirin, a broad spectrum antiviral compound, when tested against Junin virus (JV) (Arenaviridae); a good antiviral activity against measles virus (MV) (Paramixoviridae), with SI values also higher than ribavirin used as reference drug, and a similar or lower activity against herpes simplex type 1 and 2 (HSV-1 and HSV-2) (Herpesviridae) when compared to foscarnet or acyclovir, respectively. Structure activity relationship studies (SAR) are analyzed, in order to detect which stereochemistry, type and position of functional groups are needed to develop a selective class of virus inhibitors.