Anti-Infective Agents in Medicinal Chemistry

ISSN: 1871-5214

Anti-Infective Agents in Medicinal Chemistry
Volume 7, Number 3, July 2008

Contents


Anti-inflammatory Properties of Lactic Acid Bacteria: Current Knowledge, Applications and Prospects Pp. 148-154
Jean Guy LeBlanc, Alejandra de Moreno de LeBlanc, Gabriela Perdigón, Anderson Miyoshi, Tatiana Rochat, Luis Bermudez-Humaran, Philippe Langella, Fernando Sesma and Vasco Azevedo
[Abstract]


Antimicrobial Host Defence Peptides of Human Neutrophils – Roles in Innate Immunity Pp. 155-168
Å. Björstad, K.L. Brown, H. Forsman, C. Dahlgren, A. Karlsson and J. Bylund
[Abstract]


Targeting Bacterial Metalloenzymes: A New Strategy for the Development of Anti-Infective Agents Pp. 169-179
Jean-Yves Winum, Stephan Köhler, Andrea Scozzafava, Jean-Louis Montero and Claudiu T. Supuran
[Abstract]


Peptidoglycan Glycosyltransferase Inhibition: New Perspectives for An Old Target Pp. 180-192
Mohammed Terrak
[Abstract]


Multivalent Presentation Strategies in Novel Inhibitors of Bacterial (Toxin) Adhesion and Synthetic Vaccines Pp. 193-200
Roland J. Pieters and Rob M.J. Liskamp
[Abstract]


HIV-1 Infection: Recent Developments in Treatment and Current Management Strategies Pp. 201-214
Christine Armbruster
[Abstract]


Design and Synthesis of Imidazole and Benzimidazole Derivatives as Antifungal Agents Pp. 215-218
S. Khabnadideh, Z. Rezaei, A. Khalafi-Nezhad, K. Pakshir, A. Roosta, and Z. Baratzadeh
[Abstract]




Abstracts


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Anti-inflammatory Properties of Lactic Acid Bacteria: Current Knowledge, Applications and Prospects
Jean Guy LeBlanc, Alejandra de Moreno de LeBlanc, Gabriela Perdigón, Anderson Miyoshi, Tatiana Rochat, Luis Bermudez-Humaran, Philippe Langella, Fernando Sesma and Vasco Azevedo

Lactic acid bacteria (LAB) represent a heterogeneous group of microorganisms that are naturally present in many foods. Some selected strains are frequently added as probiotics in order to confer specific benefits to consumers.

Many studies have shown that LAB possess therapeutic properties since they are able to prevent the development of some diseases, as shown mostly on animal models for cancer, infections and gastrointestinal disorders such as intestinal inflammation.

They have been shown to regulate mucosal immune responses by modulating the production and liberation of regulatory agents such as cytokines by the host. Some of these cytokines, such as the anti-inflammatory interleukin-10 (IL-10), modulate the inflammatory immune response, thus immunomodulation is a mechanism by which LAB can prevent certain inflammatory bowel diseases (IBD).

Since oxidative stress participates to the inflammatory processes and to the appearance of damages in pathologies of the gastrointestinal tract of humans such as IBD, LAB could also prevent inflammation by eliminating reactive oxygen species (ROS) through the activity of antioxidant enzymes.

Engineering LAB to produce either antioxidant enzymes (such as catalases and superoxide dismutases) or anti-inflammatory cytokines (such as IL-10) is a strategy currently exploited by several groups. These novel strains have successfully been used to prevent inflammatory bowel diseases in animal models and could be evaluated in human clinical trials.

Here, we present an overview of the current knowledge of the mechanisms by which LAB can be used to prevent undesired intestinal inflammatory responses.


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Antimicrobial Host Defence Peptides of Human Neutrophils – Roles in Innate Immunity
Å. Björstad, K.L. Brown, H. Forsman, C. Dahlgren, A. Karlsson and J. Bylund

The innate immune system is an old defence mechanism that in primitive organisms consists mainly of humoral components like antimicrobial peptides. Many of these peptides share features such as size, cationicity, amphipathicity and kill microbes primarily by lysing the cell membrane. In more evolved organisms, humoral factors are supplemented by cellular components such as professional phagocytes, but the antimicrobial peptides are still important for host defence. Neutrophils are professional phagocytes that in humans contain two different classes of classical antimicrobial peptides belonging to the cathelicidin family and the α-defensin family, respectively. In addition to these two main groups of polypeptides, neutrophils are also rich in antimicrobial proteins. It is becoming increasingly clear that the antimicrobial peptides of neutrophils not only contribute to phagosomal killing, but also function as regulators of immunity; therefore the alternative name host defence peptides is more appropriate. The question whether antimicrobial host defence peptides are primarily immunomodulatory or antimicrobial in vivo has not been conclusively determined. At some locations in the body, e.g. in a phagosome, their effect is likely directly antimicrobial, whereas their immunomodulatory functions are probably more important at other sites. This review will provide a background to the field of antimicrobial peptides including their common features, mechanisms of killing and availability in nature. It will focus on the antimicrobial peptides present in human neutrophils and special emphasis will be given to the functional dualism displayed by many peptides giving them the ability to modulate the immune response in addition to being directly antimicrobial.


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Targeting Bacterial Metalloenzymes: A New Strategy for the Development of Anti-Infective Agents
Jean-Yves Winum, Stephan Köhler, Andrea Scozzafava, Jean-Louis Montero and Claudiu T. Supuran

Metalloenzymes are widespread proteins, ubiquitous in all life kingdoms, being involved in various biosynthetic processes. Some of them have been extensively studied in mammals and there are excellent examples for mechanism-based inhibitor design. α—Carbonic anhydrases (CAs), matrix metalloproteinases (MMP), or angiotensin-converting enzyme (ACE), among others, are clinically exploited targets in the treatment or prevention of a variety of diseases such as congestive heart failure, hypertension, glaucoma, epilepsy, and cancer among others. The potential of metalloenzymes as anti-bacterial targets has been taken in consideration only recently. As approximately 3-5% of the bacterial genome encodes metalloenzymes, prokaryotic metalloenzymes such as Peptide Deformylase (PDF), α- β- and γ-CAs and Histidinol Dehydrogenase (HDH), have emerged as new promising antibacterial targets in the search of novel anti-infective agents that lack cross-resistance to existing drugs. Several of these enzymes are required for growth and virulence in several pathogenic species. Their inhibition therefore constitutes an important new approach which has been already successfully applied to the discovery of antibacterial agents active in vivo. This review illustrates and describes the progress which has been made in the design and the discovery of selective inhibitors of bacterial metalloenzymes as new antibacterial agents.


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Peptidoglycan Glycosyltransferase Inhibition: New Perspectives for An Old Target
Mohammed Terrak

Peptidoglycan cell wall is an essential polymer for growth and development of most bacteria. The glycosyltransferase domain of bifunctional class A penicillin-binding proteins and monofunctional GTs proteins catalyze the polymerization of uncross linked glycan chains of the peptidoglycan whereas the penicillin-binding transpeptidases catalyze the cross-linking between peptides of neighboring glycan strands.

The biosynthesis of the peptidoglycan has been and remains an attractive target for antibacterial interventions. β-lactams and glycopeptides are the best known antibiotics that interfere with peptidoglycan polymerization. However, bacterial resistance limits the effectiveness of these antibiotics and represents a major public health problem. The first step of peptidoglycan polymerization catalyzed by the glycosyltransferases (GTs) is a validated target which is still underexplored. Moenomycin (not used in human therapy) is the only known natural inhibitor which specifically binds to the glycosyltransferases, but its clinical use is hampered by poor bioavailability.

The last few years saw big advances in the isolation and characterization of active glycosyltransferases enzymes mainly due to the availability of the lipid II substrate and analogues. Recently, the chemical synthesis of moenomycin, and the metabolic pathway of moenomycin biosynthesis have been described. At the same time, the X-ray structures of two GTs were determined including a complex with moenomycin. Glycopeptide and moenomycin derivatives which directly bind to the glycosyltransferases were developed and found to be effective against resistant pathogens. High-throughput screen of small molecules library leads to the discovery of non-natural GT inhibitors. These progresses, which will undoubtedly be helpful in the development of new GT inhibitors, are discussed.


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Multivalent Presentation Strategies in Novel Inhibitors of Bacterial (Toxin) Adhesion and Synthetic Vaccines
Roland J. Pieters and Rob M.J. Liskamp

Multi-arm constructs were synthesized and used in three different contexts, all involving pathogenic bacteria. Glycodendrimers containing either the GM1os ligand or its greatly simplified relative galactose, were found to be very strong cholera toxin inhibitors, especially at higher valencies. Related glycodendrimers containing the galabiose epitope were strong inhibitors of the adhesion of the bacterial pathogen Streptococcus suis. Finally, a synthetic vaccine against Bordetella pertussis was prepared by conjugating three different relevant peptidic epitopes to a single scaffold.


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HIV-1 Infection: Recent Developments in Treatment and Current Management Strategies
Christine Armbruster

Twenty-four years after the identification of HIV-1 as causative agent of the acquired immunodeficiency syndrome (AIDS) the pandemic continues to call for novel drugs and for new management strategies. Several steps in the HIV-1 replication cycle are potential targets for treatment interventions. Twenty-five compounds are approved by the FDA but there is still urgent need for new classes of antiretroviral drugs. Major concerns are long-term toxicity and development of resistant HIV-1 strains. Currently treatment regimens are combinations of inhibitors of two viral enzymes – the reverse transcriptase and the protease. According to their mechanism of action antiretroviral substances can be divided into the following groups: 1.) Nucleoside reverse transcriptase inhibitors. 2.) Non-nucleoside reverse transcriptase inhibitors. 3.) Nucleotide reverse transcriptase inhibitors. 4.) HIV-1 protease inhibitors. 5.) Entry inhibitors. 6.) Integrase inhibitors, and 7.) Maturation inhibitors.

Further subjects of investigation are the development of an AIDS vaccine and the evaluation of preventive strategies like pre-exposure prophylaxis and male circumcision. In contrast to the favourable results of the male circumcision studies the recent suspension of two vaccine trials, the STEP and the Phambili trial, and of the first placebo-controlled study of a vaginal microbicide for prevention of HIV-1 acquisition represents a serious draw back in the fields of vaccine development and prophylaxis.

This review summarizes the following topics: 1.) Natural history and immune pathogenesis of HIV-1 infection. 2.) Development of antiretroviral therapy and its viral targets. 3.) Mechanisms of action of antiretroviral drugs. 4.) Approved and novel compounds of existing and new classes. 5.) AIDS vaccine development. 6.) Management strategies with respect to antiretroviral therapy and HIV-1 transmission.


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Design and Synthesis of Imidazole and Benzimidazole Derivatives as Antifungal Agents
S. Khabnadideh, Z. Rezaei, A. Khalafi-Nezhad, K. Pakshir, A. Roosta, and Z. Baratzadeh

Two different series of N-substituted heteroaromatic compounds related to clotrimazole structure were synthesized. In one series ortho-cholortrityl moiety of clotrimazole was replaced by trityl, mono or dimethoxy trityl (series c). In the second series the imidazole ring of clotrimazole was also replaced by benzimidazole (series d). Chemical structures of all the new compounds were confirmed by spectrophotometric methods. These compounds docked into the active site of MT-CYP51 (PDB code, 1E9X) using Autodock tools software. They showed good affinity for the enzyme comparable to clotrimazole. Antifungal activities for these compounds were evaluated against Trichophyton mentagrophytes, Microsporum gypseum and Candida albicans using PDA as media, CHCl₃ or DMSO as solvents and agar dilution assay as method. In this method 1-triphenylmethyl-imidazole (1c), 1-(bis-4-methoxyphenyl)-phenylmethyl-benzimidazole (6d) and 1-(4-methoxyphenyl)-diphenylmethyl-imidazole (2c) showed 100%, 90% and 70% activity respectively. In the second step all of the derivatives also were evaluated against Trichophyton rubrum, Microsporum canis and Epidermaphyton floccosum using PDA medium by agar dilution method. In this method 1-triphenylmethyl-imidazole (1c) and 1-(bis-4-methoxyphenyl)-phenylmethyl-benzimidazole (6d) showed 100% and 1-(4-methoxyphenyl)-diphenylmethyl-imidazole (2c) and 1-(bis-4-methoxyphenyl)-phenylmethyl-imidazole (3c) more than 75% activity against the fungi. Then the most active analogues (1c, 2c and 6d) were tested in RPMI 1640 medium which showed desirable biological activity in comparison to clotrimazole.