Frontiers in Natural Product Chemistry: Volume 6

Atta-ur-Rahman

• Publisher: Bentham Science Publishers
• Year: 2020
• ISBN:
  9789811448461
• Topic: Medicina
• Subtopic: Farmacologia

Frontiers in Natural Product Chemistry is a book series devoted to publishing monographs that highlight important advances in natural product chemistry. The series covers all aspects of research in the chemistry and biochemistry of naturally occurring compounds, including research on natural substances derived from plants, microbes and animals. Reviews of structure elucidation, biological activity, organic and experimental synthesis of natural products as well as developments of new methods are also included in the series. The sixth volume of the series brings five reviews covering these topics: - Plant protein hydrolyzates from underutilized agricultural and agroindustrial sources: production, characterization and bioactive properties - New developments in the quinolone class of antibacterial drugs - Structure of fine starch prepared via a compressed hot water process - Major metabolites of certain marketed plant alkaloids - Natural products in cancer chemoprevention and chemotherapy

New Developments in the Quinolone Class of Antibacterial Drugs

Neslihan Demirbas^*, Ahmet Demirbas

Karadeniz Technical University, Department of Chemistry, 61080 Trabzon, Turkey

Abstract

The increasing drug resistance and the insufficiency of the newly developing antibiotics constitute a serious and growing health threat in the world. Especially Gram (-) bacteria acquire genetic material encoding antibiotic resistance by multiple mechanisms. Development of novel antibacterial agents with little tendency to bacterial resistance is, therefore, an important and challenging topic in the medicinal chemistry, and synthetic organic chemistry is an indispensable part of the design and synthesis of efficient antibacterial drug candidates. Among the broad-spectrum antibiotics, fluoroquinolones constitute the most attractive drugs in the anti-infective chemotherapy field. These antibiotics target the bacterial type II topoisomerase enzymes (DNA gyrase and topoisomerase IV) which are essential enzymes involved in bacterial cell growth and division. Since their advent, they were widely applied to treat infections. Unfortunately, most of them suffered from the resistance problem by mutations in the bacterial targets due to their wide use. Recently, the synthetic organic and medicinal chemists focused their research on the design of new fluoroquinolones with improved features by molecular hybridization technique. One of the most promising approaches aiming to combat resistant pathogens is the design and synthesis of new hybrid molecules in which different pharmacophore groups with different modes of action are joined together using a flexible linker. This strategy supplies a way to improve traditional drug combination therapies simplifying optimization of the pharmacokinetics/pharmacodynamic (PK/PD) profile, efficacy at both targets is usually synergistic.

Keywords: Aminoglycoside, Drug resistance, Flavonoid, β-Lactam, Macrocyclic, Molecular hybridization, Oxazolidinone, Pyrazole, Pyrazine, Pyrimidine, Quinolone, Triazole.

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^* Corresponding author Neslihan Demirbas: Karadeniz Technical University, Department of Chemistry, 61080 Trabzon, Turkey; Tel/Fax: [phone]; E-mail: [email protected]

INTRODUCTION

In recent years, the growing incidence of virulent bacterial resistance towards the present antibacterial agents has become the most serious clinical and socio-

economic problem worldwide [1^-3]. Although, The World Health Organization, has described the antibiotics as “miracle weapons giving an opportunity to combat with infectious diseases”, a large majority of clinically effective drugs actively used to treat bacterial infections have become less effective due to the increasing antimicrobial resistance [4^-9]. Moreover, the treatment of infectious diseases is more difficult in immunodeficient patients, such as those infected with tuberculosis, HIV etc [9]. Multidrug resistant Gram (+) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermis (MRSE), vancomycin-resistant Enterococci (VRE), cephalosporin resistant Streptococcus pneumoniae are leading significant morbidity and mortality of the infected patients [10^-12]. Another pathogen, penicillin resistant S. pneumoniae has been reported to cause approximately 3 million deaths each year worldwide because of pneumonia, meningitis and sepsis, which are responsible for serious upper airway infections, such as sinusitis and otitis media [13^-16].

Microorganisms develop resistance to drugs via various mechanisms, such as overexpression of drug efflux transporters, like multidrug and toxic compound extrusion (MATE) transporters [17], changes in the target sites of antibiotics [18], optimization of the enzyme (such as β-lactamase) activity resulting in inactivation of antibiotics [19], spontaneous chromosomal mutations [20], and horizontal transfer of genetic elements [21]. Inhibition of the activity of drug efflux transporters appears to be an encouraging strategy for renovating the activity of a drug that is the substrate of these efflux pumps [22].

Keeping all this in mind, it is clearly seen that the development of wholly novel drug discovery methodologies and the optimization of available antibacterial agents have become a crucial and challenging task for the effective treatment of bacterial infections. However, the development of completely new antibacterials suitable for therapeutic applications has not been as successful as expected, and despite a tenfold increase in spending for Research-Development studies in the pharmaceutical industry, the number of leader molecules has remained nearly stable.

To improve the therapeutic profile of the existing drugs by several manipulations in their structures or to design their novel analogs has become one of the most promising strategies for the development of new antibacterial drugs. This strategy has been widely admitted since it does not entail to discover novel scaffolds or validation of new biological targets, which has been accepted as an extremely difficult and time-consuming procedure [27].

In recent years, in order to overcome the “drug resistance nightmare”, the concept of “molecular hybridization” based on the combination of...