INTRODUCTION:

Mycobacteria are a genus of acid-fast bacilli belonging to the family Mycobacteriacae, which include the organisms responsible for tuberculosis as well as other epic and less common diseases. Earlier, tuberculosis or TB (short for tubercle bacillus) also known as phthisis, phthisis pulmonalis or consumption, is a common and in many cases fatal infectious diseases caused by various strains of mycobacteria, usually known as Mycobacterium tuberculosis¹ (M.tb.). Tuberculosis (TB) is a common deadly infectious disease usually affecting the lungs and also attacks other parts of the body².

Control of tuberculosis is continuously ignoring by the society, since 1960s, inadequate management and ill-focused national tuberculosis control programmes, are the main cause to increase the rate of mortality and relapse cases in TB³. The World Health Organization (WHO) tuberculosis programme estimates that one third of world’s population is infected with Mycobacterium tuberculosis. Worldwide 8 million people is registered by tuberculosis morbidity, amongst, 2.9 million people’s mortality rate was contributed by developing countries and mostly found between the ages of 15-59 years.

TB kills more than three million people every year worldwide, constituting about 25% of avoidable adult deaths in the developing world. Without urgent action, it is estimated, 70 million people may die from TB within the next two decades. In 1993, the WHO took an unprecedented step and declared tuberculosis is a global emergency^4-8. As per the literature review, still some bacterial pathogens are very lethal to human life. Some example are methilin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Streptococcus viridians and some gram negative bacterial organism are Proteus vulgaris, Neisseria meningitides, Salmonella typhi, Haemophilus influenza and Neisseria gonorrhoeae.

Antibacterial drugs are the greatest contribution to the 20^th century by (Infectious diseases of the society of America) IDSA. Their importance is magnified in the developing countries, where infective diseases predominate.

Drugs in this class are designed to inhibit/kill the infecting organism and to have minimal effect on the recipient. This type of therapy is generally called chemotherapy which has come to mean ‘treatment of systemic infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the host’.

Initially the term 'chemotherapeutic agent' was restricted to synthetic compounds, but now since many antibiotics and their analogues have been synthesized, this criterion has become irrelevant; both synthetic and microbiologically produced drugs need to be included together. It would be more meaningful to use the term “Antimicrobial agent” (AMA) to designate synthetic as well as naturally obtained drugs that attenuate microorganisms^9-12.

Available Treatment on tb and Bacterial Pathogens:

Drug therapy treatment on TB has been greatly hampered by the development of multi-drug-regimen (MDR-TB) and the lack of new classes of drugs. In fact, no new drugs have been developed in last two decades.The only change in the treatment of TB has been strategy of using direct observed therapy short course (DOTS) with an emphasis on patient centered care. Additionally, the course of treatment has been reduced through the use of drug combinations to 6 months, but still patient compliance upto six months to be an serious problems regarding the treatment, which escalating the development of bacterial resistance¹³.

Here some first-line and second-line TB drug and its development are described in the following braces.

p- amino salicylic acid (PAS), developed by Lechman in 1943. A more dramatic success came when Waksman and Schatz developed Streptomycin. Further efforts led to development of thiacetazone by Domagk in 1946, a grand breakthrough got in the field of tuberculosis by Squibb, Hofmann La Roche and Bayer to discover the Isoniazid (INH) in 1952, Pyrazinamide by Kushner and colleagues in 1952, and Rifamycin by Sensi and Margalith in 1957. Ethambutol was discovered at Lederle laboratories in 1961. Therefore, newer classes of agents has been developed for targeting the Tubercle bacillus pathogen and other bacterial strains. For example, Moxifloxacin, Ofloxacin, Ciprofloxacin, PA-824 and TMC-207 and many more are the different classes of TB and other bacterial drugs which are used as second-line categories as an alternatives of first line TB drug regimen. Amongst these classes, fluoroquinolone prescribed many physicians in Asia as well as North America continent for the treatment of TB as well as other deadliest bacterial pathogens because of its less resistant properties, less adverse effects, less drug interaction, shortening the treatment, and good bioavailability as compared to first-line TB drug^14,15.

Development of quinolone:

The evolution of quinolone actually emanated from the discovery of Nalidixic acid (1) in 1962 as a by-product of antimalarial research, the first representative of the quinolone which was found effective against some gram-negative microorganisms and possessed pharmacokinetic properties for treating urinary tract infections (UTIs), gastrointestinal infections, respiratory tract infections (RTI), sexually transmitted diseases (STD), skin infections and many more ¹⁶.

A breakthrough was achieved in the early 1980s by fluorination of the quinolone structure at position 6 and introduction of a piperazine substitution at position 7 resulting in derivatives called fluoroquinolones with high potency, expanded spectrum, and slow development of resistance, better tissue penetration and good tolerability.

Flumequine was the first fluoroquinolone which was patented in 1973, after that many fluoroquinolones have been patented and are still used today, including norfloxacin (1978), pefloxacin (1979), enoxacin (1980), fleroxacin (1981), ciprofloxacin (1981) and ofloxacin (1982). An advantage of these compounds over previous ones is their broad spectrum. A big revolution was made in 1980 is when an analog of Nalidixic acid, enoxacin was derived with significantly increased spectrum of activity against Gram negative or Gram positive bacteria ^17-19.

Quinolone consist of bicyclic ring structure (2) and different functional groups are substituted at positions which are shown in structure²⁰.

The structure, activity and relationship of fluoroquinolones have been investigated, the C-7 position of fluoroquinolone posses the great impact on potency, spectrum, solubility and pharmacokinetic has not been precisely defined. The oximes converted FQs derivatives shows the antibacterial activity. Substituted oximes attached to the piperazine ring at C-7 position were developed and evaluated antibacterial activity²¹.

Some literature having accounted on fluoroquinolones with phenacyl bromide, and mainly claimed the good antimicrobial properties of their novel synthesized compounds. Therefore, the present work has also been planned to synthesize the novel fluoroquinolone derivatives with phenacyl bromide. In general, Phenacyl bromide is a class of aromatic ketone which was first reported by Cowper R. M. and Davidson L. H. in 1943. It is a colorless to brownish solid crystalline, amorphous and powerful lachrymator derivatives, useful precursor to other organic compounds. Phenacyl bromide is a useful reagent for the identification of organic acid by conversion to crystalline phenacyl esters²². It is prepared by the bromination of acetophenones.

Some literatures have to suggest the oximes conversion of ketone group, developed antibacterial and anti mycobacterial agents.^23-24

Chemistry of Quinolone:

Quinolones are a group of synthetic antibacterial agents structurally related to Nalidixic acid. This first 4-quinolone also known as naphthyridine carboxylic acid was succeeded by molecules with minor modifications, including compounds such as oxolinic acid, cinoxacin, pipemidic acid and others.

All quinolone with antibacterial activity have a 4-quinolone nucleus with a nitrogen atom at position 1, a carboxyl group at position 3 and a ketone at position 4. Some of these molecular substitutions should not be altered as they would interface with or reduce markedly the basic mode of action of the drug. These are positions 2, 3 and 4. The four other positions can receive a wide range of potential substituent^25,26.

Structure, Activity and Relationship of Quinolone^27,28

Position 1.

An earlier study indicated that substitution at the N-1 position is important for antibacterial activity. Most of the marketed quinolones, such as norfloxacin, pefloxacin, and enoxacin, have an ethyl group at the N-1 position. Introduction of a t-butyl group at N-1 produced quinolones with enhanced activity against gram positive bacteria with minor reduction of activity against gram negative bacteria.

Position 2.

Very few modifications have been explored at position 2. Cinoxacin, which has a nitrogen atom in position 2, has improved pharmacokinetic properties. No clinical study on these compounds has been reported.

Position 3 and 4:

Positions 3 and 4, having a link between the carboxylic acid group and the keto group, are generally considered necessary for the binding of quinolones to DNA gyrase. Position 4 has not been extensively explored, and replacement of the 4-keto group with other groups so far has led to inactive compounds.

Position 5:

Limited investigations have been done on the C-5 position. Small substituents, such as nitro, amino, halo, and alkyl groups, have been synthesized. The C-5-amino substitution may enhance absorption or tissue distribution. Although some reports have suggested that substitution at the C-5 position reduces antibacterial activity.

Position 6:

Various C-6 substituents, H, Cl, Br, F, CH₃, CN, NO₂ etc. the addition of a fluorine atom resulted in a dramatic increase in anti-bacterial potency. Fluoro group at C-6 seems to improve both the DNA gyrase complex binding and cell penetration of the corresponding derivatives with no substitution at C-6.

Position 7.

Modification at the C-7 position of the quinolone molecule has been extensively studied. Norfloxacin, having a C-7-piperazinyl group in addition to a C-6 fluorine substituent, has antibacterial potency far superior to that of the earlier classical quinolones against gram-positive and gram-negative bacteria. In general, quinolones with small or linear C-7 substituents (H, Cl, CH₃, NH₂CH₂CH₂NH₂, NHCH₃, and NHNH₂) possess moderate to weak biological activities.

Position 8:

Many modifications investigated at the C-8 position, replacement of C-8 with a nitrogen atom or substitution with a halogen atom may provide clinically useful quinolones. In general, when compared with analogs with no substitution at the C-8 position, C-8-fluoro or chloro derivatives are more active In-vivo, owing to better oral absorption.

Mechanism of Action of Fluoroquinolone

The FQs inhibit the enzyme bacterial DNA gyrase, which nicks double-stranded DNA, introduces negative supercoils and then reseals the nicked ends. This is necessary to prevent excessive positive supercoiling of the strands when they separate to permit replication or transcription. The DNA gyrase consists of two A and two B subunits: The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then A subunit reseals the strands. FQs bind to A subunit with high affinity and interfere with its strand cutting and resealing function. Recent evidence indicates that in gram-positive bacteria the major target of FQ action is a similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after DNA replication. Greater affinity for topoisomerase IV may confer higher potency against gram-positive bacteria. The bactericidal action probably results from digestion of DNA by exonucleases whose production is signalled by the damaged DNA. In place of ON A gyrase or tope isomerase IV, the mammalian cells possess an enzyme topoisomerase II (that also removes positive supercoils) which has very low affinity for FQs hence the low toxicity to host cells^29,30.

CONCLUSION:

This review is an attempt to provide the information about fluoroquinolone. The fluoroquinolones have good bactericidal and sterilizing activities against Mtb and are potent synthetic antibacterial agents with broad spectra, including most urinary tract and gastrointestinal tract bacterial pathogens. The potential adverse aspects associated with their use in the disease merit further exploration and evaluation in order to develop optimum regimens. Nevertheless, the fluoroquinolones offer a useful addition to our current armamentarium of antibiotics for the institutional and community management of infections.

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Received on 06.08.2020 Revised on 07.09.2020

Asian J. Pharm. Res. 2021; 11(1):55-59.

DOI: 10.5958/2231-5691.2021.00011.3