Contents
Inhibitors
of Picornavirus Replication
Pp.1-12
Guy D. Diana
Discovery,
Structure-Activity Relationships and Unique Properties of Non- Fluorinated
Quinolones (NFQs) Pp.13-25
Benoit Ledoussal, Ji-In K. Almstead, Jeffrey L. Gray, Eric X. Hu and Siddhartha Roychoudhury
Discovery
and Development of Antifungal Compounds Pp.27-71
M. Kidwai, R. Venkataramanan, S. Rastogi and P. Sapra
Interactions
Between Antimicrobial Agents, Phagocytic Cells and Bacteria Pp.73-82
W. Lee Hand
The
Role of Formyl Peptide Receptors in Microbial Infection and Inflammation Pp.83-93
Yingying Le, Ronghua Sun, Guoguang Ying, Pablo Iribarren, and Ji Ming Wang
Abstracts
[Back to top] Inhibitors of Picornavirus Replication
Guy D. Diana
This review deals with the discovery of inhibitors of picornavirus replication. These inhibitors originated from 1,3-diketone compounds as juvenile hormone mimetics. One aspect of discovering these inhibitors relied on the x-ray crystallography structure of human rhinovirus-14 and understanding the binding of inhibitors to this virus. The binding site occupied a portion of the capsid protein, referred to as the canyon, leading to a hydrophobic pocket. A series of substituted oxazolines provided the initial series amenable for optimization. This series lead first to disoxaril which was clinically evaluated. Subsequently, WIN 54954 was identified as having broader spectrum of antiviral activity. Clinically, this compound was not effective against rhinovirus 28 and 29 and was extensively metabolized in humans. The medicinal chemists addressed these issues which resulted in improvements on WIN 54954 and eventually led to WIN 63843 (Pleconaril). This compound had an impressive profile with activity against one hundred rhinovirus serotype in vitro, as well as, clinical isolates and good pharmacokinetic property. Based on these results, pleconril was evaluated clinically.
This review illustrated good
collaboration between medicinal chemists and x-ray crystallographers that lead
to the design of potent inhibitors. It also demonstrates the utilization of
understanding pharmacokinetic properties needed to achieve desired properties
of the inhibitors.
[Back to top] Discovery, Structure-Activity
Relationships and Unique Properties of Non- Fluorinated Quinolones (NFQs)
Benoit Ledoussal, Ji-In K. Almstead, Jeffrey L. Gray, Eric
X. Hu and Siddhartha Roychoudhury
The use of antibacterial
antibiotics in therapy represents a huge selection pressure for bacteria
leading to increasing levels of resistance to these agents. A more controlled
usage of these drugs may be a way to partially counterbalance this bacterial
evolution. However, the design of new agents active against resistant organisms
remains of critical importance. 6-Fluorinated quinolones, like Ciprofloxacin,
represent a very significant improvement over the first generation quinolones
(e.g. nalidixic acid) in terms of potency, spectrum and pharmacodynamic
properties. Unfortunately, once introduced in clinic, these agents faced a
rapid emergence of resistance from gram-positive organisms. The subsequent
efforts to improve the fluoroquinolones’ gram-positive spectrum were
significantly hindered by the parallel existing between the fluoroquinolones’
gram-positive potency and their genotoxicity. Challenging the 6-fluorine dogma,
it was found that by selecting the proper set of substituents at 1, 8 and 7
positions, broad-spectrum quinolones of very high gram-positive potency could
be\ obtained. The potential of this non-fluorinated series became clearer when
two independent reports showed that non-fluorinated quinolones were
consistently less genotoxic than their 6-fluorinated counterparts.
Additionally, the unique structure-activity relationships of 6-hydroquinolones
and the finding of previously unreported resistance mutations induced by these
agents are indications that these analogs may not interact with their target,
the type II bacterial topoisomerases, in a way similar to typical
fluoroquinolones. This set of unique properties makes the 6-hydroquinolones or
Non-fluorinated Quinolones (NFQs) a very appealing platform from which new
broad-spectrum agents with better potency against gram-positive pathogens can
be identified.
[Back to top] Discovery and
Development of Antifungal Compounds
M. Kidwai, R. Venkataramanan, S. Rastogi and P. Sapra
Antifungal agents constitute a major part of antiinfective drugs and have been in practice since 16th century. Antifungal agents generally belong to the class of polyenes, azoles, apart from other heterocycles, organometallics, etc. Polyenes & azoles as basic moieties act by disrupting the cell wall or cell membrane or protein synthesis. The recent increase in the number of antifungal agents and the discovery that some of the older ones have properties which allow them to be used in new ways led to the development of several new therapeutic regimes. Moreover, various modifications have been attempted to achieve an optimal blend of favourable properties together with minimal potential for undesirable side effects. Thus, it is important to learn the mode of action of these agents, their advantages, and their limitations as this information will be helpful in determining the indications for use of one regimes over the others. In this review, we summarize antifungal agents which are of utmost importance clinically.
[Back
to top] Interactions Between
Antimicrobial Agents, Phagocytic Cells and Bacteria
W. Lee Hand
Interactions between antimicrobial agents and phagocytic cells may influence the outcome of therapy for bacterial infections. An ideal antibiotic would have the desired activity against extracellular organisms, and would also enter phagocytic cells, have no adverse effect on phagocyte function and eradicate surviving intracellular organisms. Another desirable characteristic would be that antibiotic accumulated by phagocytic cells is then carried by these cells to sites of infection, where active drug could be released.
Most antimicrobial agents (especially b-lactam drugs) are unable to enter leukocytes efficiently and, therefore, fail to kill intraphagocytic organisms. Nevertheless, a few antibiotics are avidly concentrated by phagocytic cells. These include clindamycin, trimethoprim, macrolide/azolide drugs, and “newer” fluoroquinolones. Azithromycin is concentrated by human PMN to a greater extent than any other antibiotic we have studied.
Surprisingly, even antibiotics which achieve high cellular levels may fail to kill antibiotic-sensitive, intraphagocytic bacteria. One potential explanation for the failure of these drugs to kill intraphagocytic organisms is antibiotic inhibition of phagocytic cell antimicrobial function. In fact, several antibiotics (clindamycin, macrolides, trimethoprim) inhibit the oxidative respiratory burst response in these cells. This effect is due to inhibition of phosphatidic acid phosphohydrolase activity, with a subsequent decrease in generation of diradylglycerol and its activation of the NADPH (respiratory burst) – oxidase. Other drugs which alter phagocytic cell activation (e.g. pentoxifylline) may exhibit cellular interactions with the modulatory antibiotics.
Avid accumulation and prolonged
retention of certain antibiotics (e.g., azithromycin) by phagocytic cells
should allow delivery and release of active drug over time at sites of
infection (an “antibiotic delivery system”). This release of antibiotic to the
extracellular milieu would then represent a true example of targeted
antimicrobial therapy.
[Back to top] The Role of Formyl Peptide
Receptors in Microbial Infection and Inflammation
Yingying Le, Ronghua Sun,
Guoguang Ying, Pablo Iribarren, and Ji Ming Wang
Although cell surface receptors
are not usually considered to be anti-infective agents, they must be included
when they serve as extremely sensitive detectors of bacterial invaders that
alert and mobilize the innate immune host defense as is the case for the family
of formyl peptide receptors. Gram-negative bacterial-derived and synthetic
Nformyl peptides, such as fMet-Leu-Phe (fMLF), are potent chemoattractants for
phagocytic leukocytes. In human, there are at least three functional receptors
for fMLF, the highaffinity formyl peptide receptor (FPR), the low-affinity
FPR-like 1 (FPRL1), and FPR-like 2 (FPRL2). These receptors belong to the
seven-transmembrane, G protein-coupled receptor superfamily. Initially these
receptors were implicated mainly in host defense against microbial infection
based on their capacity to recognize bacterial chemotactic peptides. However,
the identification of a large number of novel ligands for formyl peptide
receptors suggests they play roles of broader biological significance. Both FPR
and, to an even greater extent, FPRL1 interact with multiple exogenous and
host-derived ligands which do not show homology in their amino acid sequences.
As a result, these receptors are involved in proinflammatory responses seen in
diverse pathophysiological states. Therefore, formyl peptide receptors may
function as a first line host defense that mobilize cells engaged in
inflammation and infection.