Anti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) - Volume 5, Issue 4, 2006

Mycobacterial infections, including tuberculosis (TB) and leprosy, are infectious diseases of global importance. Control of TB is complicated by difficulties in administrating the long-course chemotherapy regimens, the inability to eliminate latent organisms, and the increasing appearance of multidrug resistant strains of Mycobacterium tuberculosis . New drugs for the control of TB are urgently needed, including developments of short-term antibiotic regimens to minimize the emergence of drug resistance and new drugs to treat MDR-TB patients and to eradicate the latent bacteria. Recent years have witnessed emergence of many new structural classes of antimycobacterial agents, some of which exhibit promising activities against susceptible and resistant strains of M. tuberculosis. In particular, the newly discovered diarylquinoline with superior antituberculous activity and encouraging results from recent studies of nitroimidazopyrans and oxazolidinones have generated considerable excitement. Genetic and biochemical studies, facilitated by the availability of mycobacterial genomes, have provided much insight into the biosynthesis of mycobacterial cell wall and metabolic processes unique to the pathogen, which reveal many potential drug targets. Some progresses toward targeting novel enzymes or biochemical processes have been made. This review summarizes these developments. Efforts to make use of existing drugs for treatment of TB, but which are currently marketed for controlling of other infections, are discussed. In addition, mechanisms of antibiotic resistance including the mycobacterial cell wall permeability barrier and novel resistance mechanisms are also discussed.

Targeting viral proteins has led to many successful antivirals. However, such drugs have certain limitations. They rapidly select for resistance and tend to be active against only a few related viruses. And a significant time is required to identify and characterize targets encoded by new viral pathogens, a major concern in emerging diseases. As a result of such limitations, cellular proteins are now considered as potential targets for antivirals. Drugs targeting cellular proteins required for several viral functions are less likely to promptly select for drug-resistance and more likely to be active against a variety of unrelated viruses, which commonly required the same cellular proteins. They could also be promptly tested against any emerging viral pathogen, as even distantly related viruses commonly require the same cellular proteins. Cellular cyclin-dependent kinases (CDKs) are required for the replication of many viruses, and specific pharmacological CDK inhibitors (PCIs) are proving to have only limited side effects in clinical trials against cancer. In the last years, PCIs have been found to inhibit replication of several wild-type and drug-resistant viruses. Two PCIs, roscovitine and flavopiridol, were recently proven active in a mouse model of HIV-induced disease. Significant progress has been made toward understanding the antiviral mechanisms of PCIs. Roscovitine was found to act by a unique mechanism, which requires no specific viral proteins but is specific for viral genomes. Consequently, mutations in viral genes cannot easily overcome inhibition by PCIs; no PCI-resistant viral mutant has yet been identified. Owing to the strong antiviral potential shown in cultured cells, their apparently relative safety in animal models and clinical trials (against cancer), and their unique antiviral mechanisms, PCIs are tentatively scheduled to enter clinical trials as antivirals in the near future.

The intensive usage and the efficacy of quinoline and artemisinin antimalarials have led scientists to focus mainly on these two families of compounds resulting in the other classes of antimalarial drugs being ignored. Recently atovaquone, a hydroxy-naphtoquinone derivative, was reported as an effective antimalarial drug against the multidrugresistant parasite with a novel drug mechanism. This discovery, which emerged from earlier studies, opened a new approach for the design of new quinone antimalarials. Other well known anthraquinone antibiotics such as tetracycline and doxycycline have been in use in malaria prophylaxis for more than three decades. This review aims to explore the background to the discovery of existing quinone antimalarials, and the advance in the chemistry and biochemistry of synthetic and naturally occurring quinones with antimalarial activity. Reactions and metabolism of antimalarial quinones in animals and men are considered, focusing on compounds that are or have been used to treat human malaria, with an emphasis on the relationship between metabolism and biological effects.

Antisense DNA and RNA are valuable tools to inhibit expression of a target gene in a sequence-specific manner. These molecules are not only widely used for gene functional study but also for therapeutic purpose. The strategy for therapeutics is attributed to its specific inhibition of gene expression of pathogens or disease-causing genes. Three types of anti-mRNA strategies can be distinguished, including antisense oligodeoxynucleotide (AODN), nucleic acid enzymes, and double-stranded small interfering RNA (siRNA). In this article we overview the basic principles of AODN and siRNA and then focus on their potential applications in antiviral therapy including our own data on coxsackieviral infection, a common pathogen of human myocarditis. In addition, we also briefly discuss the problems and difficulties in these drug developments, which need to be overcome to achieve the final goal in clinical application.

Effective hepatitis C antiviral treatment is important given the significant global morbidity and mortality from liver-related complications. Therapy for hepatitis C has advanced remarkably in the past two decades starting with interferon- alpha (IFN) monotherapy, followed by genetically engineered recombinant interferons (consensus IFN alpha) and subsequently IFN alpha in combination with the nucleoside analog ribavirin. The current gold standard is a combination of long-acting pegylated interferon (PEG-IFN) with ribavirin achieving a sustained virological response (SVR) with acceptable safety profiles in 54-66% of patients. These therapies have significantly contributed to our armamentarium against hepatitis C virus infection. Despite this success some subgroups have lower response rates (i.e. previous IFN nonresponders, patients with genotype 1 or cirrhosis). Moreover, the question of a “true SVR ” has been raised. Recent studies confirming detection of residual HCV RNA using ultra-sensitive polymerase chain reaction (PCR) based assays in patients many years after complete clinical resolution of chronic hepatitis C raise concerns whether these patients have actually been cured. In this paper we review the natural history, epidemiology and basic virology of hepatitis C. Current treatments and long-term benefits of achieving a SVR, including the antiviral and anti-inflammatory effects of IFN are also explored. Finally, we review the current understanding of persistent occult viremia in patients apparently cleared of HCV after achieving SVR with antiviral treatment.

Alterations in drug transport are a major cause of chemotherapy failures due to nonspecific resistance mechanisms. These mechanisms involve several ABC transporter proteins among which the P-glycoproteins have been the most extensively studied in vertebrates. Increased Pgp expression and/or activity in organisms leads to resistance to many chemically unrelated compounds and therapeutic agents. Such resistance has been observed in cancer and in other diseases due to infectious and parasitic pathogens. Most of the available information on these transporters has been obtained from genetic analyses, although useful data for understanding the cellular mechanisms of such resistance remains limited. As resistance affects several types of organism comparative information on the function and activity of these cellular pumps in various biological environments would be welcome. As such, nematodes represent a possible model. Recent data have been obtained for efflux function and modulation by different molecules in these invertebrates. The observed data are summarized here and the future of these studies is discussed.

Invasive fungal infections are a frequent and important complication of modern medicine and remain important causes of morbidity and mortality, particularly in immunocompromised patients. In recent years, the existing antifungal armamentarium has been increased by new drugs and/ or improvement in older drugs. In this review, we summarise the current knowledge of the mechanisms of action and resistance of both new and old antifungal drugs available for the treatment of systemic mycosis. We present in addition, a summary of the results of our studies concerning the mechanism of action of antifungal agents and detection of in vitro resistance of some important human fungal pathogens.