Current Pharmaceutical Design - Volume 7, Issue 5, 2001

A vast array of fluoroquinolones having excellent broad-spectrum activity form an invaluable part of the present anti-infective armory of the clinicians. A number of these compounds are todays blockbusters of the antibacterial market due to their therapeutic efficacy having tolerable side effects and thus challenging the predominance of well established beta-lactam antibiotics which are becoming more prone to the resistant pathogenic bacteria. Since the discovery of nalidixic acid the development of fluoroquinolones has experienced an exponential growth and is being continued with more vigor to obtain better drugs having multifunctional action. This article attempts to review the current developments of the chemical and biological aspects of fluoroquinolones in a chronological manner touching upon their antibacterial properties based on the structure activity relationship while pointing out to their mode of action. It also provides an insight into a variety of approaches resulting in elegant manipulations of their basic skeleton and some breakthroughs in their synthetic strategies of a few widely used drugs, which had helped in accelerating their market growth as well as continuing research for newer fluoroquinolones. Since the mode of action of fluoroquinolones being different from beta-lactams and their transportation to the target site is slow several dual action quinolonyl-beta-lactams (Penicillins, Cephalosporins, Penems, Cephems, Carbapenams etc.) have come as a major breakthrough among the hybrid antibiotics . While focusing on the multifunctional activities of such compounds, this review briefly points out to the current trends in various techniques for de novo drug design and development of newer therapeutic molecules, which hold future promises in combating the fight against drug resistant bacteria as it still remains to be won.

Quinolones are a very important family of antibacterial agents that are widely prescribed for the treatment of infections in humans. Although the founding members of this drug class had little clinical impact, successive generations include the most active and broad spectrum oral antibacterials currently in use. In contrast to most other anti-infective drugs, quinolones do not kill bacteria by inhibiting a critical cellular process. Rather, they corrupt the activities of two essential enzymes, DNA gyrase and topoisomerase IV, and induce them to kill cells by generating high levels of double-stranded DNA breaks. A second unique aspect of quinolones is their differential ability to target these two enzymes in different bacteria. Depending upon the bacterial species and quinolone employed, either DNA gyrase or topoisomerase IV serves as the primary cytotoxic target of drug action. While this unusual feature initially stymied development of quinolones with high activity against Gram-positive bacteria, it ultimately opened new vistas for the clinical use of this drug class. In addition to the antibacterial quinolones, specific members of this drug family display high activity against eukaryotic type II topoisomerases, as well as cultured mammalian cells and in vivo tumor models. These antineoplastic quinolones represent a potentially important source of new anticancer agents and provide an opportunity to examine drug mechanism across divergent species. Because of the clinical importance of quinolones, this review will discuss the mechanistic basis for drug efficacy and interactions between these compounds and their topoisomerase targets.

Helicobacter pylori infection is a major cause of many diseases of the gastrointestinal tract, including gastritis, non-ulcer dyspepsia, peptic ulcer disease, and gastric cancers. It is estimated that more than half of the human race is affected by this organism. Although effective treatments are available which will eliminate the organism in about 90percent of cases in developed countries, the pandemic occurrence of Helicobacter pylori infection coupled with its ability to develop resistance to our current arsenal of antimicrobial regimens and subsequently reinfect patients makes the pathogenic potential of this microorganism a major global health concern. Provided is a review of the current and evolving therapeutic regimens used in the eradication of Helicobacter pylori, the difficulties associated with in vitro drug screening, as well as potentially new therapeutic targets. In addition, the discovery, the unique physiology, biochemistry, and pathogenicity of this remarkable microorganism is examined.

Immunocompromised patients are well known to be predisposed to developing invasive fungal infections. These infections are usually difficult to diagnose and more importantly, the resulting mortality rate is high. The limited number of antifungal agents available and their high rate of toxicity are the major factors complicating the issue. However, the development of lipid-based formulations of existing antifungal agents has opened a new era in antifungal therapy. The best examples are the lipid-based amphotericin B preparations, amphotericin B lipid complex (ABLC Abelcet), amphotericin B colloidal dispersion (ABCD Amphotee or Amphocil), and liposomal amphotericin B (AmBisome). These formulations have shown that antifungal activity is maintained while toxicity is reduced. This progress is followed by the incorporation of nystatin into liposomes. Liposomal nystatin formulation is under development and studies of it have provided encouraging data. Finally, lipid-based formulations of hamycin, miconazole, and ketoconazole have been developed but remain experimental. Advances in technology of liposomes and other lipid formulations have provided promising new tools for management of fungal infections.