Current Medicinal Chemistry - Anti-Infective Agents - Volume 2, Issue 1, 2003

Volume 2, Issue 1, 2003
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Inhibitors of Picornavirus Replication
By G.D. DianaThis 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.
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Discovery, Structure-Activity Relationships and Unique Properties of Non- Fluorinated Quinolones (NFQs)
Authors: B. Ledoussal, J-I.K. Almstead, J.L. Gray, E.X. Hu and S. RoychoudhuryThe 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.
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Discovery and Development of Antifungal Compounds
Authors: M. Kidwai, R. Venkataramanan, S. Rastogi and P. SapraAntifungal 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.
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Interactions Between Antimicrobial Agents, Phagocytic Cells and Bacteria
By W. HandInteractions 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 β-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.
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The Role of Formyl Peptide Receptors in Microbial Infection and Inflammation
Authors: Y. Le, R. Sun, G. Ying, P. Iribarren and J. WangAlthough 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.
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