Development Of Tuberculosis Treatment: Fluoroquinolone Literature Review Example

{Author Name [first-name middle-name-initials last-name]}
{Institution Affiliation [name of Author’s institute]}

Introduction 3

History of TB disease 3
Why it is necessary to develop novel anti-tuberculous agents 4
Classification of fluoroquinolone 5
Mechanism of action 5
Classification and Recent updates in Fluoroquinolones 6
Quinolones: Structural features and method of synthesis 8
Structure of FQs 8
Structure-Activity Relationship 8
Bacterial resistance 9
Synthesis of Fluoroquinolone drugs 9
Levofloxacin 11
Moxifloxacin 12
Trovafloxacin 12
Conclusion 13

References 14

List of Figures
Figure 1: Basic mechanism of action of FQs 6
Figure 2: First generation quinolones7 6
Figure 3: Second generation FQs 7 7
Figure 4: Third generation of FQs 4,7 7
Figure 5: Fourth generation FQs 1,4,7 8
Figure 6: Basic structure of Quinolone 7 8
Figure 7: Gould-Jacobs method of FQ synthesis 7 10
Figure 8: Modified Gould-Jacob method 7 10
Introduction
Tuberculosis is the foremost infectious cause of death triggered by Mycoplasma tuberculosis. According to the report of CDC, TB has impacted nearly one third population of the world. The data estimated in 2013 indicate that around 9 million people got infected with TB, while death toll was 1.5 million worldwide. TB in HIV-positive people acts as a leading cause of death. Fluoroquinolone (FQ) is a recent class of drug that has shown promising impact against TB. FQ are wide ranging antibiotics that exhibit potent activity against gram-negative bacteria.1 FQ has favorable pharmacokinetic and drug interaction profiles. FQs have been used for preventive therapy, empirical treatment of TB including the retreatment of patients with relapsing TB. FQs are well-tolerated and well-absorbed antibiotics with a broad range spectrum of activity. 2
This review highlights the history and impacts of TB disease as an epidemic and effective medication for TB infection. Fluoroquinolone is considered an effective drug class and three agents that belongs to this class are described on the basis of their chemical properties. The drugs belonging to Fluoroquinolone class are Levofloxacin, Moxifloxacin, and Trovafloxacin.
History of TB disease
M. tuberculosis TB has surged in epidemics magnitude during 18th and 19th centuries. According to Daniel, the genus of mycobacterium is 150 million years old. The existence of Mycobacterium tuberculosis strain has been proved through extracting its DNA from 1000 years old mummies and archeological remnants from East Africa. 3Pathogenesis work on TB started in 1865 with the demonstration of transmissibility of infection. 3The next breakthrough towards TB treatment was the discovery of bacillus as an etiologic agent by Robert Koch in 1882. In 1907, a tuberculin skin test was developed that successfully detected infection in an asymptomatic subject. After the discovery of its pathogen, the health measures were supplemented with health care units. BCG vaccination was implemented for preventive care from World War 1 era. 3 The innovation of streptomycin in 1944 and isoniazid in 1952 changed the scenario. In 1948 UNICEF initiated a campaign under which nearly 30 million people were tuberculin tested and 14 million got vaccinated. Now WHO offered policy guidelines for TB prevention, and encouraged ambulatory therapies, and recommends BCG vaccination for newborns. 3 FQ was discovered in 1962 4 and since 1980’s it is continually investigated for its anti-TB activity.2
Why it is necessary to develop novel anti-tuberculous agents
M. tuberculosis shows a gradual growth pattern with variation in its metabolic activities according to the time and environment. It is divided into two subpopulations; one subpopulation is metabolically active, and replicates while other does not. The mutations in chromosomes at single-nucleotide polymorphisms (SNPs) result in drug resistance.1,2,5 The development of multidrug-resistant mutants is the primary concern of research and management strategies associated with TB. Low efficacy and toxic drug can not deal with the increasing drug-resistant organisms.5To avoid the development of drug-resistant mutants in TB treatment combination chemotherapy is prescribed. A survey conducted by WHO, in 1994 to 1993 in 35 countries illustrated that developed resistance to a single drug is 12.6% while multiple drug resistance is 2.2% among prevalent cases. Mostly multiple drug resistance is shown against isoniazid and rifampicin. Global health problems of TB are increasing worldwide. The increasing frequency of multiple drug resistant TB and covalence of TB with HIV has led to discovering novel active drug agents. It is an essential need to develop efficient, non-toxic and anti-tuberculous agents to fight newly developed drug-resistant TB strains. 2
Classification of fluoroquinolone
FQ is a family of antibacterial agents that possess bactericidal activity. FQs are used against gram-negative bacteria such as Pseudomonas and Mycobacterium species. The newly developed FQs have a broader spectrum; these are effective against gram-negative, gram-positive, anaerobic and aerobic organisms. 4
Mechanism of action
Quinolones act by inhibiting the bacterial type II topoisomerase DNA gyrase enzyme that is involved in DNA replication, recombination, and recovery. Thus intervening the Gyrase activity quinolones hamper the bacterial growth. Quinolones’ particular affinity towards metal ions facilitates its attachment with DNA-gyrase complex using a metal ion, Magnesium. 4First a double-stranded DNA is sliced and a momentary covalent bond is formed between 5’phosphates of DNA strands with Tyr-122 residues of two enzymatic A subunits (Fig 1). This complex made up of DNA, enzyme and drug are comparatively stable and blocks the reconstruction of the broken DNA strands.6
Figure 1: Basic mechanism of action of FQs
Classification and Recent updates in Fluoroquinolones
First Quinolone derivative was nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxilyc acid) with restrained activity. These derivatives show a narrow spectrum and were specifically developed for Enterobacteriaceae. These are more suitable for urinary antiseptics due to its pharmacokinetics. Since that time a range of quinolones has been developed.1,4,7
Figure 2: First generation quinolones7
These derivatives are categorized as the first generation quinolones. The efficacy of the first generation led to the invention of next or second generation that had a broader spectrum with potent antibacterial capabilities. They were effective on gram positive and gram negative bacteria. First fluoroquinolone was launched in 1980 with the name as Norfloxacin, which was formed by substituting C-6 with fluorine and C-7 with piperazine. 1,4,7
Figure 3: Second generation FQs 7
Third-generation FQs are levofloxacin, moxifloxacin, and gatifloxacin. Their expanded spectrum covers a range of gram-positive and gram-negative bacteria, penicillin-sensitive and resistant organisms. 4,7
Figure 4: Third generation of FQs 4,7
Trovafloxacin is the member of the fourth generation with considerable antimicrobial activity. 1, 4
The fourth generation FQs shows a similar mechanism of action by inhibiting A-subunit of DNA-gyrase enzyme and other bacterial effects like neurotoxicity, phototoxicity, and cartilage toxicity. 7
Figure 5: Fourth generation FQs 1,4,7
Quinolones: Structural features and method of synthesis
Structure of FQs
Quinolone has a bicyclic structure consisting of 4-piridinona ring attached to an aromatic ring. 4- piridinona ring depicts an acid at position 3, unsaturation at position 2-3, and a substituent at nitrogen-1.1,6,7
Figure 6: Basic structure of Quinolone 7
Structure-Activity Relationship
Studies indicate N-1 substitution is significant for Anti-bacterial activity. Many quinolones contain substituent at this position as ethyl (norfloxacin), fluoroethyl, vinyl, chloroethyl, aminoethyl, cyclopropyl (ciprofloxacin), and t-butyl. Position 2 acquires C-2 hydrogen (R2=H). It has not much value though several compounds with C-1 and C-2 have illustrated biological activity. Position 3 and 4 share a link of carboxylic group and the keto group, and this position is essential for making DNA-gyrase-complex. Position 4 has not illustrated much potential as the substitution at this position resulted in inactive compounds. C-5 amino group substitution improves the tissue distribution and absorption. Substituents for C-6 position are H, Cl, Br, F, CH3, etc., out of which fluorine substituents delivered high anti-bacterial potency. C-6 substitution by Fluorine can improve DNA gyrase complex binding (up to 17 folds) and cell penetration (70 times). C-7 is the major point that led to designing new derivatives. It has piperazinyl group with fluorine at C-6 that has superior anti-bacterial potency. C-8 methoxy or ethoxy group expand the spectrum of activity and effective against anaerobes.4,7
Bacterial resistance
Bacterial resistance to quinolone is found in gram-positive and gram-negative bacteria, and the resistance is resultant of alterations to quinolone or a development of efflux mechanism. Bacterial resistance is also known to develop due to changes in bacterial permeability and efflux pump developments. The resistance is also known to occur with antimicrobial agents that are unrelated to quinolones. In order to determine the effectiveness of agents, the bacterial resistance and pharmacokinetics of each quinolone must also be considered.4
Synthesis of Fluoroquinolone drugs
The most common method of developing FQs is Gould-Jacobs method (Fig 7)7. Several other approaches for making quinolones are Ullmann-type cyclization and Suzuki`s procedure. The main steps of synthesis methods involve a carboxylic ester hydrolysis and nucleophilic substitution of the halogen atom by precursor agent of R-7 of a piperazinyl derivative. Gould-Jacobs method is appropriate for N-1 alkyl substituent. In this synthesis, 4-hydroxyQuinolones are developed from anilines and diethyl ethoxy malonate via cyclization process of an intermediate anilinomethylenemalonate. After the formation of intermediate hydrolysis and decarboxylation take place. 6,7
Figure 7: Gould-Jacobs method of FQ synthesis 7
Figure 8: Modified Gould-Jacob method 7
A modified approach of Gould-Jacob method involves the use of monosubstituted aniline as a basic substance (Fig. 8). Through this implementation, the N-1 Amine alkylation can be blocked. It requires a potent acid for stimulation of cyclization, such as polyphosphoric acid. The final product is N-1-alkyl-4-oxoquinolone-3-carboxylate ester. This method is valuable in generating naphthyridines and pyridopyrimidines through a suitable substitution in aminopyridines and aminopyrimidines. 6,7
Levofloxacin
Brand name: Levaquin ®, Third generation FQ, and (S) enantiomer of ofloxacin. 8The chemical name of levofloxacin is (-)-(S)-9-fluoro- 2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrates and the empirical formula is C18H20FN3O4 • ½ H2O. It is orally administered and shows half-life of 6 hours and molecular weight: 370.38.1,7,8
Moxifloxacin
It is a third-generation FQ illustrating 12 hours half-life. Available under the brand name: Avelox ®, VIGAMOX® It possess 8-methoxyl group with a C-7 diazabicyclononyl ring. Chemical name is l-Cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolol[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid, monohydrochloride and formula is C21H24FN3O4•HC1. Molecular weight is 437.91,7,8
Trovafloxacin
It is a fourth generation FQs available under brand names Trovan ®. Chemical name is (1α, 5α, 6α)-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, monomethanesulfonate and formula is C20H15F3N4O3•CH3SO3H. Its molecular weight is 512.46 with 7.8 hours half-life. It has a unique 8-naphthyridine nucleus that differs it from other FQs..1,6,
Conclusion
This literature review provides the basic information on tuberculosis history and impact worldwide. Review focuses on the drug-resistant strains and the need of updated medication against pathogen. The structure, mechanism and synthesis method of FQs is described. FQs are effective and active anti-microbial agents that have exhibited a promising treatment therapy for TB patients. The third and fourth generation FQs namely Levofloxacin, Moxifloxacin and Trovafloxacin are effective and updated and efficient version of FQ.
References
King, DE.; Malone, R.; Lilley, SH. Am Fam Physician 2000, 61, 2741-2748.
Berning, S. Drugs 2001, 61, 9-18.
Daniel, TM. Respiratory Medicine 2006, 100(11), 1862-1870.
Soni, K. Indo Global Journal of Pharmaceutical Sciences 2012, 2(1), 43-53
McGrath, M; Pittius, NC; Helden, PD; Warren, RM; Warner, DF; J Antimicrob Chemother 2014, 69, 292–302
Brightly, KE; Gootz, TD. Journal of Antimicrobial Chemotherapy 1997, 39, 1–14
Lucia, P. Chem Inform 2013, 44, no-no.
Ocana, J.; Barragan, F.; Callejon, M.; De la Rosa, F. Microchimica Acta 2004, 144, 207-213.