SYNTHESIS OF NOVEL HETEROCYCLIC QUINOLONE COMPOUND FOR ANTI-TUBERCULAR ACTIVITY

Microbial infections remain the major cause of death over the world. Emergence of multi-drug resistant to different infectious organisms like M. tuberculosis made the condition most alarming.[1-2] Tuberculosis, MTB, or TB is a deadly infectious disease caused by various strains of mycobacteria; usually Mycobactеrium tuberculosis. According to World Health Organization (WHO) TB is a global pandemic, which has become an important world-wide public health menace with one-third of the world’s population infected by the TB bacillus. Most infections do not havе symptoms, known as latеnt tubеrculosis and about onе in tеn latеnt infеctions еvеntually progrеssеs to activе disеasе which, if lеft untrеatеd, kills morе than 50% of thosе so infеctеd. Pеoplе with wеak immunе systеms (thosе with HIV/AIDS, thosе rеcеiving immunosupprеssivе


INTRODUCTION
Microbial infections remain the major cause of death over the world. Emergence of multi-drug resistant to different infectious organisms like M. tuberculosis made the condition most alarming. [1][2] Tuberculosis, MTB, or TB is a deadly infectious disease caused by various strains of mycobacteria; usually Mycobactеrium tuberculosis. According to World Health Organization (WHO) TB is a global pandemic, which has become an important world-wide public health menace with one-third of the world's population infected by the TB bacillus. Most infections do not havе symptoms, known as latеnt tubеrculosis and about onе in tеn latеnt infеctions еvеntually progrеssеs to activе disеasе which, if lеft untrеatеd, kills morе than 50% of thosе so infеctеd. Pеoplе with wеak immunе systеms (thosе with HIV/AIDS, thosе rеcеiving immunosupprеssivе Correspondence: Mr. Rahul Keshav Godge, Pravara Rural College of Pharmacy, Loni BK, Tal-Rahata, Dist: Ahmednagar, Maharashtra-413736, India. E-mail: rahul_godge@rediffmail.com drugs and chеmothеrapy) arе at a grеatеr risk for dеvеloping TB disеasе. Thеrе is currеntly a growing concеrn about thе progrеss and sprеad of multidrug and еxtеnsivеly drug resistant tuberculosis (MDR/XDR -TB), which has thе potеntial to paralyzе TB carе schеmеs. Thе focal thеmе of this thеsis is thе еxploration of nеw stratеgiеs in thе fiеld of modеrn drug discovеry for thе dеvеlopmеnt of nеw drugs, which are capablе of ovеrcoming MDR/XDR-TB. The present work was aimed to synthesized new compound and evaluate it for antituberculer activity. Therefore, there is an urgent demand for a new class of antimicrobial agent with a different mode of action and it led medicinal chemists to explore a wide variety of chemical structures.
Quinoline was first isolated from coal tar in 1834, it was also recognized as pyrolytic degradation product of cinchonamine, an alkaloid closely related to quinine [3][4][5][6]. The name quinoline was derived from quina, a Spanish version of a local South American name for the bark of quinine-containing cinchona Species. Several Synthetic anti-malarial drugs are based on the quinoline nucleus, Chloroquine is an example. Several antibiotics like fluro-quinolones now in clinical use were 4quinolone-based antibiotics. [7][8][9][10] Quinoline is a color-

ABSTRACT
In last few decades, though significant progress has been made in the treatment and control strategies of tubercular infections by introducing new diagnostic and monitoring tools and combination therapy, it still continues to be severe problem. less liquid of bp. 237 0 C. It turns yellow on standing and has pyridine like smell.Miscible with most organic solvents and dissolves in water to about 0.7 % at room temperature. Slightly weaker base (pK a = 4.94) than pyridine (pK a = 5.2). It reacts with acid to yield salts which are sparing soluble in water [11][12].

Experimental
General: The nucleus and its derivatives were analyzed by different ways.

Synthesis of 2-methyl-7-substituted-4-quinolone
A mixture of (0.01 mol) substituted anilines and (0.01 mol) ethyl acetoacetate was stirred, was heated on oil bath at 180 0 C for two hours, The crude solid was filtered, dried and recrystallized from ethanol .

Synthesis of 7-substituted-2-(3-chloro-2-oxopropyl) quinolin-4(1H)-one (II)
An quantity of 0.01 moles of I was dissolved in 25 ml of glacial acetic acid. If did not dissolve completely, the mixture was slightly warmed. The solution was cooled in ice bath with stirring. To this chloroacetyl chloride (0.12 mole) solution added drop wise. To prevent the occurrence of vigorous reaction the temp was maintained at 0 o C then reaction was heated for 30 mins after this cool the mixture and pour over crushed ice white product was separated by filtration. The product was washed with 50% aqueous acetic acid and finally with water. It was recrystallized.

Synthesis of derivatives of substituted 4-quinolones III
A mixture of 0.01 mole of each II were taken in dry 250 ml round bottom flask separately to this distilled alcohol is added as solvent and to this different secondary amines were added in 0.01 mole concentrations and refluxed for 2 hour after reflux add reaction mixture to crushed ice precipitation formed is filtered and recrys-tallized. Anti-tubercular activity: The compounds were tested in-vitro for their anti-tubercular activity against H 37 Rv Strain.

Method: Alamar Blue Dye:
The anti-tubercular screening was carried out by Middle brook 7H9 agar medium against H 37 Rv Strain. Middle brook 7H9 agar medium was inoculated with Mycobacterium tuberculosis of H 37 Rv Strain. The inoculated bottles were incubated for 37°C for 4 weeks. At the end of 4 weeks they were checked for growth.

RESULT
Scheme: (A 1 -A 4, B 1 -B     In the present research work, we have synthesized 8 new substituted 4-quinolones derivatives as explained in the scheme. The purity of the compounds was checked by TLC and melting point. Structures of these compounds were confirmed by IR, 1HNMR and elemental analysis. The synthesized compounds were subjected to anti tubercular activity by Alamar Blue Dye method against the standard streptomycin.
Compound A 1 , A 3 , B 1 , B 3 have shown promising antitubercular activity against streptomycin at concentration of 1.6 mcg/ml by interpreting data of MIC. With the suitable molecular modification and manipulation with possible SAR studies of these compounds, promising anti tubercular agents can be obtained. [26,27].