We are IntechOpen, the world’s leading publisher of Open Access books Built by scientists, for scientists 4,000 116,000 120M Open access books available International authors and editors Downloads Our authors are among the 154 TOP 1% 12.2% Countries delivered to most cited scientists Contributors from top 500 universities Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI) Interested in publishing with us? Contact [email protected] Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com 12 Quinolones: Synthesis and Antibacterial Activity Pintilie Lucia National Institute for Chemical-Pharmaceutical Research and Development, Bucharest Romania 1. Introduction After the concept of selective toxicity in chemotherapy was introduced at the beginning of the 20th century, (Ehrlich, 1913), classes of substances with antibacterial properties, produced by microorganisms or created through synthesis were obtained. After the discovery of penicillin, the first antibiotic introduced in clinical use in man in 1940s, a large number of different types of antibiotics were produced. Antibiotics such as beta-lactams, macrolides, aminoglycozides and tetracyclines were discovered and introduced during an extremely short period. These were obtained either by isolation from fungi or by chemically modification of the naturally isolated substrates. These dominated the antimicrobial industry, while synthetically obtained substances only played a minor role. (Chu & Fernandes, 1991) In 1962, G. Y. Lesher and his collaborators introduced the first quinolone derivative, nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxilyc acid), (1, Lesher et al. 1962) which had moderate activity against gram-negative organisms and was used for treating urinary tract infections. In the following years, a large gamma of derivatives from common elements were synthesized, which could be grouped by: cinoline (cinoxacin), pyrido-pyrimidine (pipemidic acid; piromidic acid), naphthyridine (nalidixic acid) and quinolones (oxolinic acid, miloxacin , tioxacin, etc.). These derivatives, with differentiated structures, have 2 common pharmacological properties, which allowed them to be classified as first generation biologically active derivatives with quinolone structure. The two common characteristics for first generation quinolones are: - a narrow antibacterial spectrum, designed especially for enterobacteriaceae; - a pharmacokinetic which allows for rapid elimination and reduced tissue absorption, only allowing them to be used as urinary antiseptics. O O O O COOH O COOH COOH N O N O N CH3 N N C2H5 C2H5 C2H5 Nalidixic Acid Cinoxacine Oxolinic Acid 256 Antimicrobial Agents O O O COOH COOH N O COOH N N N N O N N N N C H OCH3 2 5 HN C2H5 Miloxacine Piromidic Acid Pipemidic Acid Fig. 1. First-generation quinolones. The success of first generation quinolones spurred the research in this area, which led to the obtainment through synthesis, after 1980, of a new series of compounds with stronger antibacterial properties and a broader spectrum of antibacterial activity which included gram positive and gram negative organisms, and which where defined by their ability to be applied on all localized infections. Koga and his collaborators introduced Norfloxacin into clinical use in 1980, the first quinolone with a fluorine atom substituted at the C-6 position and a piperazine C-7. Norfloxacin (Koga et al. 1980) was the first quinolone with increased antimicrobial activity, acting on a large spectrum of gram positive and gram negative microorganisms, including Pseudomonas aeruginosa. O O O F COOH F COOH F COOH N N N N N N HN C2H5 CH3 N C2H5 HN Norfloxacin Pefloxacin Ciprofloxacin O O O F COOH F COOH F COOH N N N N HN F C2H5 N N CH3 N F CH2CH2F CH3 Lomefloxacin CH3 N NHCH3 Fleroxacin Amifloxacin O O O F COOH F COOH F COOH N N N N N N N HN C2H5 CH3 N O CH3 CH3 N S Enoxacin Ofloxacin Rufloxacin Fig. 2. Second-generation quinolones. Research in the field of derivatives with a quinolone structure have lead to new compounds obtained recently, which have been classified as third and fourth generation systemic quinolones, largely effective against Staphilococcus aureus. Their large antibacterial spectrum includes anaerobes, Chlamydia and Mycoplasma. (Brighty & Gootz, 2000) Quinolones: Synthesis and Antibacterial Activity 257 O F COOH O CH3 O F COOH F COOH NH CH3 N N CH3 N N CH3 N N OCH3 HN OCH3 HN Balofloxacin Gatifloxacin Grepafloxacin O NH2 O O F COOH F COOH F COOH CH3 H2N N N N N N HN F N O CH3 CH3 N OCH3 CH3 Gemifloxacin Sparfloxacin Levofloxacin O O O F COOH F COOH F COOH NH2 N CH3 N N H2N N N N F HN F O CH3 Pazufloxacin Temafloxacin F Tosufloxacin F Fig. 3. Third- generation quinolones. The four generations have the following common aspects: an identical mechanism of action by inhibition the A subunit of DNA-gyrasa, an exclusively chromosomal bacteria resistance and some similar bacteria effects: photo toxicity, neurotoxicity, cartilage toxicity. O O O F COOH F COOH F COOH H N N N H2N N N N N H2N F Cl S Cl R H F H2N S Trovafloxacin F Clinafloxacin Sitafloxacin O O F COOH F COOH H H HN S N N HN S N N S OCH3 S Cl H H Moxifloxacin BAY y 3118 Fig. 4. Fourth- generation quinolones. Until now a large number of antibacterial substances belonging to the above mentioned class have been used in medicine. Quinolones are used when treating infections of the urinary tract, the respiratory tract, intestinal infections, ear/nose/throat infections, STD’s, soft tissue and skin infections, meningitis caused by gram negative and Staphilococci bacteria, liver and bile infections, septicemia and endocarditis, prophylaxis and surgical infections and on patients with immune deficiencies. 258 Antimicrobial Agents The mechanism of action of quinolone antibacterial agents involves the inhibition of DNA gyrase (a bacterial topoisomerase II) resulting in a rapid bactericidal effect. The antibacterial activity of quinolones (measured in terms of MIC), however, is the result of the combination of bacterial cell penetration and DNA gyrase inhibitory activity. The antibacterial activity of quinolones depends not only on the bicyclic heteroaromatic system combining the 1,4-dihydro-4-pyridine-3-carboxylic acid moiety and an aromatic ring, but also on the nature of the peripheral substituents and their spatial relationships. These substituents exert their influence on bacterial activity by providing additional affinity for bacterial enzimes, enhancing cell penetration or altering the pharmacokinetics. The research for an ideal quinolone continues worldwide. Such a quinolone must be biologically active on a large spectrum of gram positive and gram negative bacteria, aerobes and anaerobes and mycobacteria, must have as few side effects as possible, excellent solubility in water and oral bioavailability. In figure 5, the most common synthesized chemical variations obtained during the research for new quinolones with antibacterial activity, are visible. NH (8-F) 2 H H, Hal.,CH3, OH Hal CH O O 3 NH2 R5 O NH NH O S R COOH 6 5 4 3 S 6 S 7 8 1 2 S R7 A N CH3 R HN N R1 C2H5, C2H4F, NHCH3, t-Butil R O N R N F F NH2 R CH, N, R CHal, CNO , 2 N N CNH2, CCH3, S S N CH2NHR R COCH3, CCH2F O CH3 O S N N CH3 CH3 R O CH3 NH2 N N NR CH3 R R NH2 O N CH3 N CH3 N NH N N O O CH3 N R N N R N R Fig. 5. Structural variations of the most recent quinolones. Quinolones: Synthesis and Antibacterial Activity 259 2. Quinolones: Structural features and method of synthesis 2.1 Structural features Quinolone derivatives are an important class of antibacterial agents with wide action. Basic structure of these compounds (Figure 6) is a bicyclic structure, which contains a ring of type A B A 4-piridinona combined with aromatic or heteroaromatic ring . The ring type 4- piridinona is a ring with absolute necessity: an unsaturation in position 2-3, a free acid function in position 3 and a substituent at nitrogen in position 1. O 5 4 CO H 6Z 3 2 B A X 7 Y N 2 1 8 R Fig. 6. Basic structure of quinolones. 2.1.1 Bicyclic quinolones Position 1 The studies on quinolones indicated that in order for the compound to have antibacterial activity, the N-1 position requires a substituent. Many quinolones contain in N-position : ethyl (norfloxacin, pefloxacin, lomefloxacin) , fluoroethyl (fleroxacin), vinyl, clloroethyl, trifluoroethyl, aminoethyl,, cyclopropyl (ciprofloxacin), t-butyl, bicyclopentyl,p- fluorophenyl,2,4-difluorophenyl (Scott 1997) Position 2 Quinolones contain at C-2 hydrogen (R =H). The replacement at hydrogen has generally 2 proven to be disadvantageous. However, some compounds containing a suitable C-1, C-2 ringhave recently been shown to possess biological activity. (Figure7 -Segawa 1992) (Figure 8 – Scott 1997) R O 5 R CO H 6 6 3 2 5 4 8 1 R 7 X N 2 R 7 2 R 1 Fig. 7. Basic structure of bicyclic quinolones. 260 Antimicrobial Agents O R CO H 6 2 R N S 7 R R = H, methyl, ethyl, substituted phenyl R = F, Cl 6 R = heterocycle 7 Fig. 8. 7-Substituted-6-halo-4-oxo-4H-[1,3]-thiazeto[3,2]quinolin-3-carboxilyc acid. Position 3 The C-3 carboxylic acid moiety is most commonly encountered. (Chu &Fernandes1991) . In the late of 1980s, a modification was described that eliminated the need for C-3 carboxylic acid. A fused izothiazolone ring was identified as serving as a carboxylic acid mimic,The compound A-62824 (Figure 9) have been found with biological activity. O O O F CO2H F CO2H F CO2H N N S N N S HN N N S HN HN O Fig. 9. Quinolones with sulfur substituent at C-2. O O F NH S N N HN Fig. 10. A-62824. Position 4 The C-4 oxo group of the quinolones nucleus is generally considered to be essential for antibacterial activity. Position 5 The choice of the C-5 substituent appears to be dictated by the the steric regulations and the nature of the N-1 and C-8 substituent (Chu &Fernandes1991). (R = methyl, halogen, amino 5 when X = CF). Quinolones: Synthesis and Antibacterial Activity 261 Position 6 The nature of the C-6 substituent have a great impact on the DNA-gyrase inhibitory activity and cell penetration. (Domagala et al. 1986). The R can be H, Cl, F, NO , NH , CN, 6 2 2 CH SCH , COCH ) (Koga et al. 1980) 3 3 3 Position 7 The choice of the C-7 substituent is a key issue which continues to guide the design of new antibacterial quinolones. The R can be substituted/unsubstituted piperazines, 7 aminopyrrolidines, aminoalkylpyrrolidines, (Figure 5) (Chu & Fernandes 1991) (Scott 1997). Position 8 The most common variations at the C-8 position is hydrogen atom (X= CH) or a nitrogen atom(a naphthyridine) (X=N). However, compact, liophilic group (X = CF,C-CF , CCl, C- 3, OCH increase the antibacterial activity. (Chu & Fernandes 1991) (Scott 1997). 3) 2.2 Method of synthesis Gould-Jacobs method The quinolones are of synthetic origin. (Chu & Fernandes, 1991). The most common synthetic methodology to prepare quinolone derivatives is Gould-Jacobs method (Figure 11). This method is used mainly for synthesis of compounds with N-1 alkyl substituents, and consists in the condensation of anilines (II) with diethyl ethoxymethylenemalonate (EMME) and cyclization of the obtained anilinomethylenemalonate. Termal cyclization can be carried out in dowterm (Koga, et al.1980), clorsulfonic acid, oleum acid or a mixture of clorosulfonic acid and oleum acid (Saukaita & Gupton, 1996). The key intermediary obtained (IV or X) will undergo a alkylation (Koga et al. 1980), cycloalkylation with bromo- cyclopropane (Kazimierozaack & Pyznar, 1987), (Sanjose&Ulpiano 1986), or with 1-bromo- 1-ethoxy-cyclopropane, arylation with para-nitro-clorofenil or 2,4-dinitro-clorofenil (Raddl & Zikan, 1989) in order to insert the substituent in position 1 of the quinolone nucleus. The ethyl esther (V) undergoes a hydrolysis reaction, and the quinoline-3-carboxylic acid (VI), following regiospecific substitution of the 7-chloro group leads to the final compounds (VIII). Figure 11 illustrates also, methods for synthesis of 1-cyclopropyl-quinolones starting to anilines of formula II.Anilines (II) is reacted with 1-bromo-1-ethoxy-cyclopropane (Ramos & Garcia 1994)(Scriewer et al. 1988) or a cyclopropyl-metalic compound (McGuirk 1989). Alternatively, N-ethyl substituted anilines of formula XV may be formed by reductive amination with an appropiate aldehyde and a suitable reducing agent: diborane, palladium on carbon with hydrogen, sodium borohydride or sodium cyanoborohidride (McGuirk 1989) (Ramos 1994). N-isopropyl substituted quinolones may be form by alkylation with isopropylbromide (Pintilie et al. Sept. 2009), (Pintilie et al, oct.2009),(Pintilie et al. 2010), of compounds IV. (Figure 11). The modified Gould-Jacobs method will also be used, where the diethyl ethoxymethylenemalonate reacts with monosubstituted N aniline (XVII) (Figure 12). The aniline (XVII) is obtained by reductive amination of ketones and aldehydes with sodium borohydride-acetic acid (Itoh & Kato 1984) or triacetoxyborohydride. (Pintilie et al.2009). (Pintilie et al. 2010). c C t a A M F 2 2Et) to provide key compound (V). ompound (HOCH=CHCO l) to produce benzoxazindione (XXII). The benzoxazindione (XXII) is then condense 232 3 321-10RCO (R= R= Cl, CClO or R= Calkyl anhen is treated with the compound :R cetate (Figure 13). 2,4,5-trihalobenzoic acid (XX) is reacted with an appropiate amin nother synthesis method requiers the reaction of isatoic anhydride with sodio ethyl ethod requiers the reaction of isatoic anhydride with sodium ethyl formyl acetate ig. 11. Gould-Jacobs method. 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The modified Gould-Jacobs method. O F CO2H F CO2H F R1NH2 R2R3CO O X I X NH X N O XX R1 R1 XXI XXIII O O F CO2Et F CO2H HOCH=CHCO2Et X N X N R1 R1 V VI O R7H F CO2H R7 N R1 VII Fig. 13. Method requiers the reaction of isatoic anhydride with sodium ethyl formyl acetate Intramolecular nucleophilic displacement cyclization route to quinolones (a) An efficient and regiospecific synthesis via an intramolecular nucleophilic displacement cyclization reaction was reported. (Chu,1985) (Figure 14). Key compund (III) can be obtained by: • reaction of benzoic acid chloride (I) with ethyl malonic acid; the compound (II) give the compund (III).(Petersen & Grohe 1984a), (Petersen & Grohe 1984b), • acetophenone (Ia) is condensed with diethyl carbonate in the presence of sodium hydride(Chu et al. 1985)