Transition Metal Complexes of Methyl-quinolino [ 3 , 2-b ] [ 1 , 5 ] benzodiazepine and Methylquinolino [ 3 , 2-b ] [ 1 , 5 ] benzoxazepine : Synthesis , Characterisation and Antimicrobial Studies

The synthesis and characterisation of title complexes of the ligand Methylquinolino[3,2-b][1,5]benzodiazepine (MQBD) and Methylquinolino[3,2-b][1,5]benzoxazepine (MQBO) are reported. The complexes have been characterized by elemental analysis, molar conductance, magnetic studies, IR, H NMR and UV-visible studies. They have the stoichiometry [ML2Cl2] where M=Co(II)/Ni(II), L=MQBD/MQBO and [MLCl2] where M=Zn(II)/Cd(II), L=MQBD/MQBO. The antibacterial and antifungal activity of the metal complexes has been investigated.


Introduction
Quinoline derivatives represent the major class of heterocycles, and a number of preparations have been known from the late 1980s.The quinoline skeleton is often used for the design of many synthetic compounds with diverse pharmacological properties.The 8-(diethylaminohexylamino)-6-methoxy-4-methyl-quinoline is highly effective against the protozoan parasite Trypanosoma cruzy, which is the agent of Chagas' disease 1 and the 2-(2methylquinolin-4-ylamino)-N-phenylacetamide is more active than the standard antileishmanial drug sodium antimony gluconate 2 .The centipede, Scolopendra Subspines mutilalns L. which is found to contain 3,8-dihydroxyquinoline called Jineol has been prescribed for tetanus, childhood convulsions and acute heart attack 3 .Cryptolepine (5methyl-5H-indolo [3,2-b]quinoline) displays a plenty of pharmacological effects, such as antimuscarinic, noradrenergic receptor antagonistic, antihypertensive, vasodilative, antithrombotic, antipyretic and anti-inflammatory properties.

Measurements
The IR spectra of ligand and its metal complexes were recorded on a SHIMADZU FTIR-8400S spectrometer with KBr pellets in the region 250-4000 cm -1 .JEOL 60 MH Z spectrometer was used for recording the proton NMR spectra employing TMS as internal reference and DMSO-d 6 as solvent.
UV-visible spectra were measured on a SHIMADZU double beam spectrophotometer using N,N'-dimethylformamide as a solvent at 10 -3 M concentration.

Antibacterial activity
Antibacterial activity of ligands and its complexes were studied against Gram positive bacteria S. aureus and Gram negative bacteria P. aerugenosa by employing paper disc method 9 .The streptomycin (100 mg) was used as a standard.For each concentration, the mean diameter of inhibition zone developed (mm) was calculated.

Antifungal activity
The antifungal studies of ligands and its complexes were tested on the fungal strains namely, C. albicans, A. flavus and A. niger in the growth media by using Batemann poisoned food technique 10 .The average percentage inhibition was calculated by using the reported method 11 .

Synthesis of Methylquinolino[3,2-b][1,5]benzodiazepine(MQBD)
The mixture of 2-Chloro-6-methylquinoline-3-carbaldehyde (1.569 g, 5 mmo1) dissolved in small amount of acetic acid and o-Phenylenediammine (0.541 g, 5 mmol) was taken in a 100 ml borosil beaker and a pinch of potassium iodide was then added.The whole mixture was made into slurry and was irradiated by placing the beaker in a microwave oven for about 10 minutes.The product obtained was poured into ice-cold water, the solid separated was filtered, dried and recrystallized (Scheme 1).

Synthesis of Methylquinolino[3,2-b][1,5]benzoxazepine(MQBO)
The mixture of 2-aminophenol (0.11 g, 1mmol), KOH (0.057 g, 1 mmol) and 2 ml of DMSO were taken in a 100 ml borosil beaker.2-Chloro-6-methylquinoline-3-carbaldehyde (1 mmol, 0.314 g) and a pinch of KI were then added.The mixture was irradiated for about two minutes in a microwave oven.The product was then hydrolyzed by pouring into icecold water.The final product separated as a solid on acidification with dilute HCl was then filtered, dried and purified (Scheme 2).

Cobalt(II) and Nickel(II) complex of MQBD and MQBO
The hot solution (0.5 mmol, 50 ml) of metal(II) chloride was slowly added to 50 ml of hot ethanolic solution of the ligand (1.0 mmol) with continuous stirring.The reaction mixture was warmed on a water bath at 60-70 o C for about 2 hours.The precipitate obtained was filtered, washed several times with absolute alcohol, finally with ether and dried.

Cadmium (II) and Zinc (II) complexes of MQBD and MQBO
The ethanolic solution of divalent metal salt (2.5 mmol) was added to a solution of the ligand (2.5 mmol) in ethanol (10 ml).The reaction was stirred for 24 h at room temperature.The solid formed was filtered and dried under vacuum.

Stoichiometry
The complexes are microcrystalline coloured powder, whose melting points are higher than the pure ligand.They are stable at room temperature and are insoluble in common organic solvents.The elemental analysis data show that they are of the types [ML 2 Cl 2 ] where M=Co(II)/ Ni(II), L=MQBD/MQBO and [MLCl 2 ] where M=Zn(II)/Cd(II); L=MQBD/MQBO.Low molar conductance values (14.45-27.4mhos cm 2 mol -1 ) of these complexes indicate their non-electrolytic nature (Table 1).

Magnetic moments
The room temperature magnetic moment value (Table 1) support octahedral geometry for Co(II) and Ni(II) complexes 12,13 .The Zn(II) and Cd(II) complexes are diamagnetic due to non availability of unpaired electrons 14 .

IR Spectra
The ligand MQBD shows bands at 1662 cm -1 and 3332 cm -1 due to ν(C=N) and ν(NH) vibrations respectively 20 .These bands are shifting in the complexes indicates the coordination of nitrogen atom of quinoline and azepine moiety with the metal ions.The IR spectra of MQBO showed absorption bands at 1025 cm -1 and 1653 cm -1 for ν(COC), ν(C=N) respectively 21 .The negative shift of these bands in the complexes indicates the sites of coordination are nitrogen and oxygen atoms quinoline and azepine rings, respectively.The important IR spectral data are shown in Table 2.

H NMR spectra
All the compounds show the 1 H NMR signals for different kinds of protons at their respective positions.The data are shown in Table 2.The 1 H NMR spectra of the ligand MQBD exhibit a singlets at 10.80 δ (s, N-H) and 8.6 δ (s, H-C=N).The 1H NMR spectra of complexes slightly changed compared to those of the corresponding ligand, and the signals appeared downfield, as expected, due to the coordination of nitrogen atoms to the metal ion [22][23][24] . 1 H NMR spectrum of MQBO ligand showed signals at 8.4 (s, 1H, H-C=N), 7.3-8.0(m, 11H, Ar-H) and 2.6 (s, 3H, CH 3 ).In the spectra of complexes, all signals remained at same position except the signal of H-C=N.This is probably due to the coordinating effect of the azepine oxygen atom.

Antibacterial Activity
The comparison of inhibition zone values for the metal complexes (Table 3) reveals that the antimicrobial activity could be mainly due to the structure of the complexes and also the oxidation state of the metal ions.These results must be directly related to the greater biological activity exhibited by the square planar Zn(II) complexes compared to the tetrahedral Cd(II) and octahedral Co(II), Ni(II) complexes.
A possible explanation for the high toxicity of metal complexes can be explained as follows.The increase in the activity of metal complexes may be due to effect of metal ions on the normal cell process.The polarity of metal ion is considerably reduced on chelation which is mainly because of partial sharing of its positive charge with a donor groups and possibly -electron delocalization over the whole molecule.Such molecule increases the liphophilic character of the metal complexes which probably leads to break down of permeability barrier of the cells resulting in interference with normal cell process 25 .Better activities of the metal complexes as compared to free ligand could also be understood in terms of chelation theory 26 , which explains that a decrease in polarizability of the metal could enhance the liphophilicity of the complexes.

Antifungal activity
The percentage inhibition values of fungicidal growth are recorded in Table 4.The screening data clearly shows that the complexes were more toxic than their parent ligand under identical experimental conditions and as the concentration of the complexes increases the inhibition of the fungal growth increases.

Table 1 .
Physical constants of ligands and its complexes.

Table 2 .
The IR and 1 H NMR spectral data of ligands and complexes.

Table 3 .
Inhibition zone of bacterial growth (mm)

Table 4 .
Percentage inhibition of fungicidal growth.