1.1 STRUCTURE AND ISOLATION OF QUINOLINE
Quinolines are interesting compounds for research in the field of chemistry, with large derivatives1 . Quinoline is a heterocyclic aromatic compound containing nitrogen as hetero atom with molecular formula C9H7N2 and characterized by double ring structure consisting a benzene ring attached to pyridine ring3. The quinoline ring system 1 is one of the three possible aza-naphthalenes, than first two being isoquinoline 2 and quinazolium cation 34.
The quinoline ring system is well established in various naturally occurring compounds, their isolation had led to many advances in heterocyclic chemistry5. Quinoline ring system was extracted from coal tar in 1834 by friedlieb Ferdinand range6 and in 1842 by Charles federic grehardt from cinchonine and quinine alkaloids from which the name of quinoline was derived 7. The word quinine is derived from spanish version of American name from the bark of quinine containing cinchona species i.e.., quina.8
1.2 CHEMICAL AND PHARMACOLOGICAL APPLICATIONS OF QUINOLINE DERIVATIVES
Quinolines and their derivatives have many chemical and pharmacological properties. Quinoline has been found to have many pharmacological activities such as anti malarial activity, central nervous system effects, parkinsons and alzheimers disease, chagas disease, epilepsy, cardiovascular activity anti mycobacterial activity etc….9,10
1.2.1 ANTI MALARIAL ACTIVITY
Malaria is one of the most widely occuring diseases in the world, mainly in saharan Africa and in some places south America and Asia11. World health organization estimated about 40% of the world’s population suffering with malaria and 300 million infections occur every year, which leads 1-3 million deaths annually12. Anti malarial activity the most important activity of quinolines, for example, quinine5 was first effective drug for malaria caused by plasmodium falciparum.13
By the 1940’s most widely used drug for malaria is chloroquine 6 later chloroquine resistant strains have develop also identified15 during the same period which acts as an anti malarial drug. Bisquinoline derivatives 9,10 were developed by raynes and co-workers which shows anti malarial activity against chloroquine resistant and chled in 195714. Mefloquine 7 analogs of chloroquine were identified in 1970’s. amidoquine 8 oroquine sensitive parasites16. Amino quinoline derivatives were developed which acts as anti malarials against malarial parasites. 17,18,19,20
1.2.2 CENTRAL NERVOUS SYSTEM EFFECTS
The major health issue in the 21st century is cognitive dysfunction which was found in various neuropsychiatric and neurodegenerative disorders like depression, schizophrenia, alzheimers disease, Parkinson’s disease, epilepsy22. Due to this many quinoline derivatives have been synthesized to treat neurological disorders23
23. 18.104.22.168 Parkinson’s and Alzheimer’s disease
Ghodsi and co-workers24 synthesized numerous 4-substituted 2,3-di aryl quinoline derivatives containing methyl sulfonyl group at para position of the 2-phenyl ring as cyclo-oxygenase-2 (COX-2) which are crucial for treatment of Alzheimer’s disease25 ; Parkinson’s disease26. Hydrogen bonding interactions promoted by carboxylic acids thus 2-(4-(methyl sulphonyl)phenyl)-3-phenyl quinoline-4-carboxylic acid shows high potency as COX-2 inhibitors whereas bulky groups show decreased potency due to lack of hydrogen bonding. Novel tacrine-8-hydroxy quinoline derivatives developed by bachiller and co-workers which show activity against Alzheimers disease.27
22.214.171.124 CHAGAS DISEASE
Chaga’s disease is caused by parasite trypanosome cruzy,which effects CNS that results in brain lesions ; encephalitis30. It is spread by insects known triatomine or kissing bugs. Treatment of Chaga’s disease involves killing of parasite in acute infection, managing signs & symptoms in further stages. Chiari and co-workers developed 8-(dimethylaminohexylamino)-6-methoxy-4-methyl quinoline show activity against the protozoan parasite thus decreasing the survival of kissing bugs thus reducing chaga,s disease infections.31
Epilepsy is chronic neurologic disorder with recurrent seizures32. There is major demand for development of anti epileptic agents, it is impossible to control every seizure with present treatments33. In recent years many modifications of quinoline ring have reported with promising anti epileptic outcomes.
Synthesis and invivo anti epileptic activity of 2-chloro quinolinyl-hydrazone was reported by kumar & co-workers. The anti epileptic activity was performed by two models of seizures in mice viz. maximal electric shock (MES) and subcutaneous pentyl enetetrazole (scPTZ). Pentyl enetetrazole ia an agent that shows activity as central nervous system stimulant.34
The results of their study shows the electron withdrawing groups (Cl, Br, F) in phenyl ring show good anti-epileptic activity and long lasting. The anti-epileptic activity reduces when CH2 or CH2O are introduced between phenyl ring and carbonyl group. Replacement of phenyl ring with an amino group results in retention of anti epileptic activity.
1.2.3 CARDIOVASCULAR ACTIVITY
Many chemical modification of quinoline ring system leads to positive results which form novel lead compounds having cardiovascular activity. Selective phosphodiesterase type-4 (PDE4) inhibitor with chronic obstructive pulmonary disorder35.
Biarylether amide quinolines act as liver X receptor agonists, dyslipidemia was developed by bernotas & co-workers. This condition is defined as abnormal concentrations of lipids in blood pasma.36
1.2.4 ANTI MYCOBACTERIAL ACTIVITY
Tuberculosis is increased due to lack of therapeutic agents. Thus, novel anti tuberculosis drugs are needed to reduce duration of treatment and to kill the mycobacterium tuberculosis effectively. So many quinoline derivatives have synthesized and tested for anti-tuberculosis activity.37,38
Many 4-amino substituted 2,8-bis (triflourometyl) quinoline derivatives and their invitro evaluation of anti-mycobacterial activity against MTB strain H37Rv39 by mital & co-workers. The most effective compound 23a series has minimum inhibitory concentration (MIC) of 3.13µg/ml and IC50 value of 3.9 µg/ml. biological studies has been revealed that the presence of diaminoalkyl chain and trifloro methyl groups in the 2- and 8- positions of quinoline ring show useful biological activity.40
1.3 SPECTRAL INTRODUCTION
The analytical information of a compound can be studied by using
• IR spectral studies.
• NMR spectral studies
I. 1H – NMR
II. 13C – NMR
• Mass spectrophotometry
Infra red spectrum (IR spectrum) give sufficient data regarding the structure of compound. This technique provides data of spectrum having a large number of absorption bands which provides data of the functional groups present in compound. Each functional group present in compound absorbs IR radiations at particular frequencies and thus produce characteristic absorption bands . These absorption bands at particular frequencies helps to identify functional groups present in compound.
• Identification and quatification of solids, liquids, or gaseous samples.
• Analysis of powders, solids, gels, emulsions, pure liquids, solutions, pastes, polymers, pure and mixed gases.
• Used for research methods, quality control methods development and quality assurance applications.
NUCLEAR MAGNETIC RESONANCE (NMR)
NMR is used in organic structure determination. It is used to study various nuclei; 1H, 13C, 15N, 19P. NMR deals with the absorption of radio frequencies of particular substances present in magnetic field. Interaction of radiation with magnetic moment of nuclei leads to absorption. A nucleus with odd mass number or odd atomic number has nuclear spin. A magnetic field is generated by spinning charged nucleus. NMR phenomenon can be governed by five factors like energy transitions, precessional frequency, precessional motion, external magnetic field & spinning nucleus. NMR spectroscopy is used to study t stereochemistry and to determine structure of the compound.
a) Proton NMR spectroscopy:
Proton NMR spectroscopy provides structural information regarding the hydrogen skeleton in molecule, which is used in structural determination of molecule. Proton NMR tells us the nature, type & number of protons attached to carbon skeleton in the molecule with the help of signals. The number of signals in the spectrum determines the number of different equivalent protons present in the molecule. The position of signals tells us the nature of protons and multiplicity of the proton determines the type of proton. Each proton will absorb different field strength giving different chemical shift values at different regions (Robert M Silverstein, Francis X Webster et al,2007).
• NMR is used to study unknown copmpounds.
• Used to determine the type of hydrogen bonding (inter or intra molecular).
• NMR is used in quantitative analysis.
• Used to study rate of reactions and activation energies.
Mass spectroscopy is used to determine the molecular mass of the compound and its elemental composition. In mass spectroscopy the molecules are bombarded with the beam of high energetic electrons. The molecules get ionized, broken into small fragments i.e., positive ions. Each ion have particular mass to charge ratio (m/z). The set of ions are analyzed based on signals by particular fragment in molecule. The largest molecule is known as base peak and its intensity is taken as 100. Removal of one electron from parent molecule leads to the formation of parent ion. The mass to charge ratio of parent ion is equal to molecular mass of that compound.(YR Sharma et al.,)
• It helps us to determine molecular mass & molecular weight of the unknown compound.
• Atomic weight can be calculated with the help of this spectroscopy.
• Used in determination of purity of compound.
• Used in detection of impurities present in the compound.
• Helps in determination of ionization potential.
• Used to study reaction kinetics & bond dissociation energies.