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Anti-Infective
Agents in Medicinal Chemistry
ISSN: 1871-5214
Anti-Infective Agents in Medicinal
Chemistry
Volume 5, Number 1, January 2006
Contents
Editorial
Azoles: Mode of Antifungal Action and Resistance Development.
Effect of Miconazole on Endogenous Reactive Oxygen Species
Production in Candida albicans Pp. 3-13
Isabelle E.J.A. François, Bruno P.A. Cammue,
Marcel Borgers,Jannie Ausma, Gerrit D. Dispersyn and Karin
Thevissen
[Abstract]
Pharmacological and Biological Activities of Xanthones
Pp. 15-31
Jean Fotie and D. Scott Bohle
[Abstract]
Cationic Surfactants and Lipids as Anti-Infective Agents Pp.
33-54
Ana M. Carmona-Ribeiro, Débora B. Vieira and
Nilton Lincopan
[Abstract]
Use of Anti-Infective Drugs in Rheumatology Pp. 55-61
Jacob N. Ablin
[Abstract]
Mechanisms of Drug Resistance in Malaria: Current and New
Challenges Pp. 63-73
P. Cravo, R. Culleton, A. Afonso, I.D. Ferreira and
V.E. do Rosário
[Abstract]
Rationale for Designing of Antigen-Specific Immune Therapy
Including Dendritic Cell-Based Therapy in Patients with Chronic
Hepatitis B Virus Infection Pp. 75-84
Sk. Md. Fazle Akbar, Hidehiro Murakami, Norio Horiike
and Morikazu Onji
[Abstract]
Natural and Synthetic Retinoids: Structural Bases and Biological
Effects of Potential Clinical Relevance for the Prevention
and Treatment of Infection-Driven Tumors Pp. 85-103
Riccardo Dolcetti, Dario Di Luca and Angel R. de Lera
[Abstract]
Recent Developments in Antimalarial Drug Discovery Pp.
105-122
A.A. Joshi and C.L. Viswanathan
[Abstract]
Abstracts
[Back to top]
Editorial
The growth theme continued its trend in all areas of anti-infectives.
While new chemical entities have recently been described in
the literature against certain molecular targets, many challenges
remain in the future.
One notable concern relates to the need of developing new
antibacterial drugs. This year in June we witnessed the approval
of Tygacil (Tigecycline) by the U.S. FDA for the treatment
of a range of bacterial infections. Tygacil belongs to a new
class of antibiotic named glycylcyclines, which have been
specifically developed to overcome the general problem of
resistance to antibacterial agents.
An interesting trend for the discovery of new antibacterial
agents continues to be based on genomics and bioinformatics
approaches. A relatively large number of novel essential targets
have been proposed. Genomic approaches, coupled with biochemical
studies, are also useful in understanding modes of action
of antibacterial agents.
Invasive antifungal infections, particularly in immunocompromised
patients, are limiting our arsenal of antifungal agents and
remain a problem of unmet medical need. New agents are clearly
needed to compliment current strategies and advances in this
area.
Many advances have been made in the area of antivirals particularly
against hepatitis C. Specifically, polymerase inhibitors from
both non-nucleoside and nucleoside classes are being disclosed
in primary publications and scientific meetings. Current Medicinal
Chemistry - Anti-Infective Agents Vol. 4, No. 2 dedicated
excellent review articles (S.M. Condon, M.G. LaPorte, T. Herbertz
p. 99 and S.R. LaPlante, M. Llinas-Brunet pp.111) on this
subject matter.
Twenty-one excellent review articles were published in four
issues of Volume 4. These reviews span all three major areas
of anti-infectives research: antivirals (11), antibacterials
and antifungals (10). The emphasis of the journal is on the
medicinal chemistry aspect of anti-infectives and promising
agents. We encourage submission of reviews on comparative
structure activity relationship analyses, technologies in
inhibiting certain targets, mechanistic studies, synthesis
and biological properties of new agents and validation of
new targets of potential therapeutic intervention, as well
as pharmacokinetic/pharmacodynamic relationships. Dr. Christopher
J. Burns served as a guest editor for Volume 4, No. 2 and
has provided external reviews on antiviral agents.
Contributors to issue 1 include: V.K. Tandon, R.B. Chhor,
J.P. Viard, L. Rossi, S. Serafini, P. Franchetti, L. Cappellacci,
A. Fraternale, A. Casabianca, G. Brandi, F. Pierige, C-F Perno,
E. Balestra, U. Benatti, E. Millo, M. Grifantini, M. Magnani,
A. Pellegrini, M. Engels, S. Coviello, F. P. Polack, S.B.
Gordon, N. French.
Issue 2: Guest Editor, C. J. Burns Contributors include:
S.M. Condon, M.G. LaPorte, T. Herbertz, S.R. LaPlante, M.
Llinas-Brunet, W. M. Kazmierski, J.P. Peckham, M. Duan, T.P.
Kenakin, S. Jenkinson, K.S. Gudmundsson, S.C. Piscitelli and
P.L. Feldman, M. Witvrouw, V. Fikkert, J. Vercammen, B. Van
Maele, Y. Engelborghs and Z. Debyser, L. Garuti, M. Roberti,
D. Pizzirani and G. Poggi.
Issue 3: E. Bacque, J.C. Barriere, N. Berthaud, G. Bou, S.Stefani,
B.J. Wilkinson, A. Muthaiyan, R.K. Jayaswal and M. Schlitzer.
Issue 4: R.S. Wallis, J.L. Johnson, B. Heldreth, E. Turos,
C. Meier, A. Meerbach, P. Wutzler, J. Vila, J. Sanchez-Cespedes,
E. Giralt, M.C. O’Sullivan.
Because of the valuable target of enhancing the communication
and feedback between all involved, the current Advisory Board
will be modified by providing a chance for new members to
participate and change some members due to the evolving nature
of review articles. We encourage greater participation by
our Advisory Board to continue advancing the journal’s
objectives. We take this opportunity to thank our past Advisory
Editorial Board Members for their efforts and welcome the
new members. Joining us as new members are: T. Abe, N.E. Allen,
R. Andersen, M.A. Avery, C.A. Bewley, M. Bos, J.D. Buynak,
L. Chan, G. Diana, E.L. Ghisalberti, W. Hillen, R.J.R. Hwu,
M.E. Jung, M. Kidwai, M. Konaklieva, V.J. Lee, S. Levy, M.L.
Nelson, D. Payne, B.M. Pinto, C.K. Sha, R. Storer.
In 2006, the journal will publish under the name Anti-Infective
Agents in Medicinal Chemistry. The list to credit for all
these achievements is long. We thank the referees for their
time and effort in reviewing the articles. The hard working
and enthusiastic team of the journal, particularly Ms. Afshan
Siddiq, is greatly acknowledged. We also thank Ms. Michele
Markey of Wyeth Research for her support.
Phaik-Eng Sum
Co-Editor-in-Chief
Tarek S. Mansour
Co-Editor-in-Chief
[Back to top]
Azoles: Mode of Antifungal Action and Resistance Development.
Effect of Miconazole on Endogenous Reactive Oxygen Species
Production in Candida albicans
Isabelle E.J.A. François, Bruno P.A. Cammue,
Marcel Borgers,Jannie Ausma, Gerrit D. Dispersyn and Karin
Thevissen
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
impor-tant 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.
[Back to top]
Pharmacological and Biological Activities of Xanthones
Jean Fotie and D. Scott Bohle
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.
[Back to top]
Cationic Surfactants and Lipids as Anti-Infective Agents
Ana M. Carmona-Ribeiro, Débora B. Vieira and
Nilton Lincopan
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 physico-chemical 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.
[Back to top]
Use of Anti-Infective Drugs in Rheumatology
Jacob N. Ablin
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 im-muno –
modulatory effects. This review covers the main events in
the development of anti – infective agents for rheuma-tology
and attempts to clarify the often enigmatic relationship between
these two seemingly unrelated fields.
[Back to top]
Mechanisms of Drug Resistance in Malaria: Current and
New Challenges
P. Cravo, R. Culleton, A. Afonso, I.D. Ferreira and
V.E. do Rosário
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 dihydrop-teroate
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 un-derstanding
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.
[Back to top]
Rationale for Designing of Antigen-Specific Immune Therapy
Including Dendritic Cell-Based Therapy in Patients with Chronic
Hepatitis B Virus Infection
Sk. Md. Fazle Akbar, Hidehiro Murakami, Norio Horiike
and Morikazu Onji
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.
[Back to top]
Natural and Synthetic Retinoids: Structural Bases and Biological
Effects of Potential Clinical Relevance for the Prevention
and Treatment of Infection-Driven Tumors
Riccardo Dolcetti, Dario Di Luca and Angel R. de Lera
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.
[Back to top]
Recent Developments in Antimalarial Drug Discovery
A.A. Joshi and C.L. Viswanathan
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.
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