Nonclassical Biological Activities of Quinolone Derivatives
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J Pharm Pharmaceut Sci (www.cspsCanada.org) 15(1) 52 - 72, 2012 Nonclassical Biological Activities of Quinolone Derivatives Abeer Ahmeda and Mohsen Daneshtalaba aSchool of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada. Received, November 3, 2011; Accepted, December 9, 2011; Published, December 9, 2011. ABSTRACT- Quinolones are considered as a big family of multi-faceted drugs; their chemical synthesis is flexible and can be easily adapted to prepare new congeners with rationally devised structures. This is shown by the description of many thousands of derivatives in the literature. Scientists could accurately describe their QSAR, which is essential for effective drug design. This also gave them the chance to discover new and unprecedented activities, which makes quinolones an endless source of hope and enables further development of new clinically useful drugs. Quinolones are among the most common frameworks present in the bioactive molecules that have dominated the market for more than four decades. Since 1962, 4(1H)-quinolone-3-carboxylic acid derivatives are widely used as antibacterial agents. Quinolones have a broad and potent spectrum of activity and are also used as second-line drugs to treat tuberculosis (TB). Recently, quinolones have been reported to display “nonclassical” biological activities, such as antitumor, anti-HIV-1 integrase, anti- HCV-NS3 helicase and - NS5B-polymerase activities. The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent and/or an antiviral agent. Indeed, quinolones’ antimicrobial action is distinguishable among antibacterial agents, because they target different type II topoisomerase enzymes. Many derivatives of this family show high activity against bacterial topoisomerases and eukaryotic topoisomerases, and are also toxic to cultured mammalian cells and in vivo tumor models. Moreover, quinolones have shown antiviral activity against HIV and HCV viruses. In this context the quinolones family of drugs seem to link three different biological activities (antibacterial, anticancer, and the antiviral profiles) and the review will also provide an insight into the different mechanisms responsible for these activities among different species. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. _____________________________________________________________________________________ INTRODUCTION Quinolones as a class of antibacterial agents have been known for over 40 years. Although Quinolones as “privileged building blocks” with considerable results in the research of new simple and flexible synthetic routes allow the antibacterial quinolones have already been production of large libraries of bioactive molecules. achieved, they are still a matter of study because of Because of their diversity, drug-like properties and the continuous demand of novel compounds active similarities to specific targets they are considered a against resistant strains of bacteria. Research efforts central scaffold to build chemical libraries with are mainly focused on obtaining new compounds promising bioactivity potential. active against very resistant bacterial strains or The first quinolone discovery, as many important acting on the mechanisms of resistance (1-4). discoveries, was a result of serendipity. Lesher et al. Currently, fluoroquinolones are approved as (1962) (1) discovered the first quinolone derivative second-line drugs by the WHO to treat TB but their as an impurity in the chemical manufacturing of a use in MDR-TB is increasing due to the fact that batch of antimalarial agent chloroquine. Since then they have a broad and potent spectrum of activity more than 10,000 quinolone derivatives have been and can also be administered orally. Moreover, they patented or published which explains the enormous have favorable pharmacokinetic profiles and good progress that has been made in understanding the absorption, including excellent penetration into host molecular mechanisms of action behind the macrophages. different pharmacological actions of this privileged _________________________________________ molecule. Corresponding Author: Mohsen Daneshtalab; Newfoundland, Canada, A1B 3V6; E-mail: [email protected] 52 J Pharm Pharmaceut Sci (www.cspsCanada.org) 15(1) 52 - 72, 2012 As of today, the potential of fluoroquinolones as positions have also been prepared by palladium- first line drugs is still under investigation (5-7). catalyzed carbonylative heterocyclization (12). Palladium cyclization enables the synthesis of The chemistry of 4-Quinolones several 4(1H)-quinolone-3-carboxylic acid The original method for the preparation of 4- derivatives in 24-82% yields. The palladium- quinolones relies on the Gould-Jacobs reaction catalyzed cyclization has the potential to between a substituted aniline and a dialkyl accommodate substituents at position 2 which in alkoxymethylenemalonate (8). turn offers flexibility for the design of quinolinone Lappin cyclization (9) results in cycloacylation derivatives as depicted in Scheme 3. on heating at a high temperature to provide the quinoline-4-one system as shown in Scheme 1. SN2 Biological targets of antibacterial quinolones alkylation at N-1 followed by ester hydrolysis Generally, quinolones directly inhibit the DNA affords the substituted 4(1H) - quinolone-3- synthesis by binding to the enzyme-DNA complex. carboxylic acid. The Gould-Jacobs approach allows Quinolones also stabilize DNA strand breaks only the introduction of primary alkyl groups, thus created by DNA gyrase and topoisomerase IV. limiting the preparation of derivatives with more Ternary complexes of drug, enzyme, and DNA complex substituents at N-1. In this respect the block progress of the replication fork. The Grohe- Heitzer cycloacylation expanded the cytotoxicity of fluoroquinolones can be explained synthetic possibilities of quinolones as depicted in on the basis of a 2-step process: i) conversion of the Scheme 2 (10). ternary complex (topoisomerase quinolone-DNA) In the Grohe-Heitzer synthesis, the active to an irreversible form, and ii)- production of a methylene in a β-ketoester is condensed under double-strand break by denaturation of the dehydrating conditions with an ortho ester resulting topoisomerase. The molecular basis necessary for in the formation of the enol ether which is further the transition from step 1 to step 2 is still unclear subjected to an addition-elimination reaction using (13). an appropriate primary amine. The product obtained is cyclised through aromatic nucleophilic Supercoiling and Topoisomerases displacement of a leaving group (typically Cl, F) at Supercoiling (14, 15) is the process in which the ortho position with respect to the activating chromosomal DNA is wound around itself making carbonyl group. Final hydrolysis of the ester it possible for the 1-2 meter long chromosome to fit function under either basic or acidic conditions within the cell, and the supercoiled DNA has an gives the quinolone-3-carboxylic acid (11). effective diameter of about 1 μm. 4(1H)-Quinolone-3-carboxylic acid derivatives containing a variety of substituents at different O O O + O O NH O NH 2 O O O 1 2 3 O O O O OH O N N H R 5 4 Scheme 1. Synthesis of 4-quinolones using the Gould-Jacobs reaction. 53 J Pharm Pharmaceut Sci (www.cspsCanada.org) 15(1) 52 - 72, 2012 O Cl 6 2 ) t E O ( O C / a N O t O E O O O O O Cl CH2(COOEt)2 HC(OEt)3 , AC2O base O Cl Cl O Cl 7 8 9 2 H N R OO OO O O OH O O base N N Cl NH R R R 5 11 10 Scheme 2. Synthesis of 4-quinolones using Grohe-Heitzer reaction. The winding and unwinding of DNA is cleavage complexes are catalytic intermediates, accomplished by a class of enzymes called present only in low concentrations and are therefore topoisomerases (topo). Supercoiling is achieved by tolerated by the cell. However, conditions that the passage of one DNA strand through another; significantly increase the physiological type I topoisomerase enzymes perform DNA concentrations or lifetime of these breaks promote passage after creating a single-strand break, while plenty of harmful side effects, including mutations, type II enzymes catalyse the passage of a double- insertions, deletions and chromosomal stranded region of DNA through a double-stranded abnormalities (16). break in the helix. The supercoiling level in living The DNA break is formed through a bacteria is determined by the balancing activities of transesterification step which leads to the topo I and a topo II enzymes. The production of attachment of the 5´- phorphoryl group on DNA to topo I and DNA gyrase is self-regulating which the hydroxyl on Tyr-122 on GyrA (18). The DNA is means that an overactivity of one encourages the cut in a sequence-specific manner, creating a 4-bp transcription of the genes for the other enzyme. The staggered break on opposite strands of the DNA. In strand passage is a critical feature to all a study by Morrison et al. (19) the cleavage of four topoisomerases as it requires the enzymes to cause double stranded DNAs was examined. Each double- breaks in the genetic material. These breaks are stranded DNA strand was cleaved between T and G stabilized by covalent bonds between the 3´ end on the one strand; however, the cleavage on the (eukaryotic topoisomerase I) or 5´ end of the newly complementary strand seemed to have no sequence formed break and the enzyme. Normally, these specificity. 54 J Pharm Pharmaceut Sci (www.cspsCanada.org) 15(1) 52 - 72, 2012 O O O O R O O CO, Pd 0 ︵ ︶ PdX N R NH R NH H 12 R 14 R O O 13 Scheme 3. Synthesis of 4-quinolone-3-carboxylic acid derivatives by palladium-catalyzed carbonylative heterocyclization. Important structural features of antibacterial iii. Positions 3 and 4 quinolones These two positions on the quinolone nucleus are essential for gyrase binding and bacterial transport It is really important to highlight the structural and no other useful substitutions have yet been requirements for a quinoline pharmacophore to reported.