Anti-Infective Agents in Medicinal Chemistry

ISSN: 1871-5214

Current Medicinal Chemistry - Anti-Infective Agents
Volume 4, Number 4, October 2005

Contents


The Role of Surrogate Markers in the Clinical Evaluation of Anti-tuberculous Chemotherapy Pp.287
Robert S. Wallis and John L. Johnson
[Abstract]


Microbiological Properties and Modes of Action of Organosulfur-based Anti-infectives Pp.295
B. Heldreth and E. Turos
[Abstract]


CycloSal-Pronucleotides of Brivudine Monophosphate – Highly Active Antiviral Agents Pp.317
Chris Meier, Astrid Meerbach and Peter Wutzler
[Abstract]


Old and New Strategies for the Discovery of Antibacterial Agents Pp.337
J. Vila, J. Sánchez-Céspedes and E. Giralt
[Abstract]


The Battle against Trypanosomiasis and Leishmaniasis: Metal-based and Natural Product Inhibitors of Trypanothione Reductase Pp. 355
Mary C. O’Sullivan
[Abstract]




Abstracts

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The Role of Surrogate Markers in the Clinical Evaluation of Anti-tuberculous Chemotherapy
Robert S. Wallis and John L. Johnson

Eradication of the pathogen has historically served as a key endpoint in clinical trials of anti-infective therapy. Studies of anti-tuberculous therapy have established the general principle that the rate of clearance of M. tuberculosis may serve as a surrogate marker for the adequacy of its eradication. The best studied of these markers is sputum culture conversion after 2 months of chemotherapy. Closely related measures include time to sputum culture conversion, and serial assessment in sputum of CFU counts, mycobacterial antigens and host cytokines. These are now supplemented by an ex vivo infection model in which the capacity of host immune mechanisms and administered chemotherapy to kill intracellular M. tuberculosis is assessed using whole blood culture. The validation of new surrogate markers that reliably predict relapse of tuberculosis is essential if the pace of clinical research in tuberculosis is to be accelerated.


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Microbiological Properties and Modes of Action of Organosulfur-based Anti-infectives
B. Heldreth and E. Turos

At least as long ago as the ancient Egyptians, sulfur-bearing natural products have been used for their potent medicinal properties. Although extracts from leeks were the earliest sulfur-containing substances to be employed for treatment of microbial and parasitic infections, a wide variety of natural and synthetically derived organosulfur compounds have been found to possess important antibiotic properties. There now exist, for virtually every class of human infection, representative examples of organosulfur anti-infective agents. By definition, these anti-infectives are compounds capable of preventing, inhibiting, or treating one or more types of infection. Except for their sometimes pungent odor and chemical instability, most antimicrobially active organosulfur compounds display few ill side effects. Given this era of drug resistance in which there is an ever-increasing demand for new antibiotics, organosulfur compounds may provide leads to novel therapies. In this review, we survey the microbiological properties and biochemical behavior of those or-ganosulfur compounds whose activity depends specifically on the reaction of the organosulfur functionality with a bio-logical target. The most common or likely mechanistic pathways by which these interactions occur are presented as a means to better understand the compounds’ modes of action, and to appreciate the opportunities that may exist towards designing yet even more effective anti-infective agents.


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CycloSal-Pronucleotides of Brivudine Monophosphate – Highly Active Antiviral Agents
Chris Meier, Astrid Meerbach and Peter Wutzler

CycloSal-BVDUMP triesters 32-34 5-[(E)-2-bromovinyl]-2'-2'-deoxyuridine (BVDU 2) have been studied with regard to their potential anti-EBV activity. In addition to the 3’-unmodified cycloSal-BVDUMP triesters 32a-f, the 3’-hydroxyl function has been esterified with different aliphatic carboxylic acids (33a-g) and α-amino acids having natural and non-natural Cα-configuration (34a-m). In addition to the synthesis of these compounds, different physicochemical properties will be reported, i.e. lipophilicity and hydrolysis behaviour. It could be shown that BVDUMP and not 3',5'-cyclic BVDUMP was delivered from most of the compounds by chemical hydrolysis in phosphate buffers at pH 6.8 and 7.3 as well as P3HR-1 cell extracts. Finally, the compounds were tested for their anti-EBV activity. As a result, the prototype compounds and particularly triesters 32c,d exhibited pronounced anti-EBV activity making these compounds promising candidates for further development. However, the 3’-ester derivatives were devoid of any antiviral activity, while the 3'-aminoacyl derivatives showed an antiviral activity, in dependence of the amino acid and the Cα-configuration. In addition, all cycloSal-BVDU phosphotriesters proved to be potent and selective inhibitors of herpes simplex virus type 1 replication. Several pronucleotide concepts will be briefly summarised but the cycloSal-pronucleotide system described in more detail is the only approach that showed an improvement in antiviral activity of the nucleoside analogue BVDU.


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Old and New Strategies for the Discovery of Antibacterial Agents
J. Vila, J. Sánchez-Céspedes and E. Giralt

In this review we have tried to present a complete and integrated picture of the old and new ways to discover antibacterial agents. The development of new antibacterial agents can be made from derivatives of known antibacterial agents or by identification of novel agents active against previously unexploited targets. The genetic and biochemical basis of resistance to most classes of antibacterial agents is now known and this has been important in the design of a rational strategy that can be used to counteract resistance. This strategy can follow two approaches: i. Modification of the basic structure of the antibacterial agent, which circumvents antibacterial resistant mechanisms, and ii. Development of a compound inhibiting the mechanism of resistance for an antibacterial agent, hence the concomitant administration of the antibacterial agent plus the inhibitor, as a co-drug, will potentiate this activity. There are also two main approaches to find new protein targets: 1. Classical and, 2. Genomic. The first includes the study of secondary metabolites of bacteria and fungi with antibacterial activity, and it has now been expanded to include plant extracts and marine macro- and microor-ganisms, as well as non-cultivable soil bacteria. Recent tools such as comparative genomic, combinatorial chemistry, and computerized modelling have helped in the development of new antibacterial agents. Finally, other approaches, such as bacteriophages, antisense RNA and proteins involved in pathogenicity to find new antibacterial drugs are currently inves-tigated.


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The Battle against Trypanosomiasis and Leishmaniasis: Metal-based and Natural Product Inhibitors of Trypanothione Reductase
Mary C. O’Sullivan

Trypanothione reductase is an enzyme that is unique to organisms belonging to the family Trypanosomatidae. Certain trypanosomatids, including trypanosomes and leishmania, are parasitic protozoa that are responsible for several devastating diseases. Trypanothione reductase plays a pivotal role in maintaining the redox balance of trypanosomatids, thus the development of inhibitors of trypanothione reductase may lead to the design of new drugs to combat diseases caused by parasitic trypanosomatids. Trypanothione reductase catalyzes the NADPH-mediated reduction of a glutathione-spermidine conjugate named trypanothione. Several classes of trypanothione reductase inhibitors have been developed and discussed in recent reviews. However, less attention has focused on the interactions of inorganic compounds with trypanothione reductase. This is an intriguing area, since many of the current drugs used to treat trypanosomatid infec-tions are metal-based complexes, containing either arsenic or antimony, and several of these compounds interact with try-panothione and/or trypanothione reductase. Thus, although the trypanocidal activities of these drugs involve several mechanisms, one site of action may be trypanothione reductase. In this review, the major diseases caused by Trypanoso-matidae, current drugs, drug resistance, and an overview of trypanothione and trypanothione reductase are summarized. Recent work on the development of metal-based inhibitors of trypanothione reductase (including platinum(II) complexes) and interactions between certain inorganic compounds (including antimony(III), antimony(V) and arsenic(III) complexes) and trypanothione are discussed. Finally, studies of a range of natural products that inhibit trypanothione reductase are summarized.