1. Novel metal- ligand complex compound of formula (I). Formula I Wherein M is metal selected from Titanium and Zirconium and X is selected from Chlorine and Bromine.

2. The novel compound as claimed in claim 1 wherein the X is Bromine.

3. The novel compounds as claimed in claim 1 wherein M is Titanium.

4. The novel compound as claimed in claim 1 wherein the compound has metal:ligand ratio of 1:2.

5. The novel compound as claimed in claim 1 wherein compound of formula I is (Z)-2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide represented by formula II

6. A process for preparing the novel compound of formula I, said process comprising: (a) Treating ethyl oxybutanoate with benene 1,2 diamine in the presence of a solvent to obtain 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one (b) Treating 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one with a chlorinating agent and a base to obtain 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine (c) Treating 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine with 4 hydroxyacetophenone to obtain 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one, (d) Treating 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one with thiosemicarbazide to obtain 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide (e) Treating 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide with a metal salt to obtain the metal complex compound of formula I.

7. The process as claimed in claim 6, wherein the chlorinating agent is selected from Oxalyl chloride, Phosphorus oxychloride, Phosphorus pentachloride, Phosphorus trichloride and Thionyl chloride.

8. The process as claimed in claim 7, wherein the chlorinating agent is Phosphorus oxychloride.

9. The process as claimed in claim 6, wherein the base is selected from benzyldimethylamine, pyridine, and imidazole , 4 dimethyl aminopyridine, methylpyridine, Aniline, trimethyl aniline, N, N dimethyl aniline.

10. The process as claimed in claim 9, wherein the base is N, N dimethyl aniline.

11. The process as claimed in claim 6, wherein the solvent is selected from benzene, toluene, hexane, xylene water, methanol, ethanol, ethyl acetate and ether.

12. The process as claimed in claim 11, wherein the solvent is xylene.

13. The process as claimed in claim 6, wherein the metal salt is Bromide or chloride of titanium or Zirconium.

14. The process as claimed in claim 13, wherein the metal salt is Titanium tetrabromide or Titanium (IV) Bromide. Dated this the 10th day of October 2024.

Description:FIELD OF THE INVENTION:
The present invention relates to novel antimicrobial compounds. In particular, the present invention provides novel Schiff base ligand and its metal complex. The Schiff base ligand and its metal complexes of the present invention are useful as antimycobacterial agents.

BACKGROND OF THE INVENTION:
Schiff bases are privileged ligands in organic chemistry. Due to their chelating properties and ability to coordinate with a wide range of transition metal ions of various oxidation states, they are considered as significant family of organic compounds. These bases and their metal complexes find use in inorganic, bioinorganic, analytical, material science, and pharmaceutical chemistry. Schiff bases and their metal complexes have been found to be useful against a variety of microorganisms also and hence are effective in treating various infectious diseases. They have also been shown to exhibit a broad range of biological activities, including antifungal, antibacterial, antimalarial, antiproliferative, anti-inflammatory, antiviral, and antipyretic properties.
US3117122A discloses Schiff base of 4-amino-3-isoxazolidone and terephthalaldehyde. The Schiff bases of the invention are strongly effective in vitro against Mycobacterium tuberculosis, and against the microbes of the pathogenic flora of the urinary tract including strains of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Pseudomonas vulgaris which are resistant to other therapeutic agents. The Schiff bases thus are indicated in the treatment of tuberculosis, and they are particularly suitable for the treatment of urinary infections.
WO2012057599 discloses hydroquinilone carboxylic acids compound as antimycobacterial agents. The document discloses the synthesis of Schiff base and mannich base. The process involves (a) synthesizing an aromatic ester derivative using an aromatic carboxylic acid and alcohol in the presence of concentrated sulfuric acid; (b) synthesizing an acid hydrazide derivative using the aromatic ester derivative from step (a); (c) synthesizing Schiff bases using the acid hydrazide derivative from step (b); and (d) synthesizing Mannich bases using the Schiff bases from step (c).
Biosciences Biotechnology Research Asia, Vol. 18(3), p. 575-583 discloses antimicrobial analysis of amino acid Schiff base and derivatized metal complexes against fungal strains, Candida parapsilosis, Candida albicans, Candida krusei, and Cryptococcus neoformans and (Gram-negative) P. aeruginosa, E. coli, S. typhimurium, and S. pyogenes, Methicillin-resistant Staphylococcus aureus (MRSA), S. mutans (Gram-positive) bacterial strains had been done by disc diffusion method following McFarland protocol. [CuLCl2] and [Cu (CH3OH)2] manifest overwhelming activity against microbes than other metal complexes of cobalt, nickel and zinc. Minimum inhibition concentration data also shows that copper complexes have the lowest MIC values against these tested microorganisms.
Asian J. Research Chem. 15(1): January - February 2022 discloses antimicrobial activities of coordination compounds of Titanium and Zirconium with Schiff base. The document discloses semicarbazide compound and the metal complex against four bacteria, i.e Escherichia coli, Staphylococcus aureus, Extended Spectrum Beta-Lactamase (ESBL), Methicillin-resistant Staphylococcus aureus (MRSA. Compounds also screened for two fungi, i.e Candida albicans and Aspergillus fumigatus
Although the literature is replete with disclosures related to antimicrobial Schiff bases, considering the rapid resistance development in the microbes, it is necessary to develop novel antimicrobial compounds which can give better antimicrobial activity.

OBJECT OF THE INVENTION:
It is an object of the present invention to provide novel antimicrobial compound.
It is another object of the present invention to provide novel antimicrobial compound with better antimicrobial efficacy and less toxicity.
It is yet another object of the present invention to provide pharmaceutical composition comprising novel antimicrobial compounds.

SUMMARY OF THE INVENTION:
Accordingly, the present invention provides novel compound of formula I

Formula I
In another embodiment the present invention provides a process for the preparation of novel compounds of formula I, said process comprising:
(a) Treating ethyl oxybutanoate with benzene 1,2 diamine in the presence of a solvent to obtain 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one
(b) Treating 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one with a chlorinating agent and a base to obtain 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine
(c) Treating 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine with 4 hydroxyacetophenone to obtain 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one,
(d) Treating 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one with thiosemicarbazide to obtain 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide
(e) Treating 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide with a metal salt to obtain the metal complex of formula I.
In yet another embodiment the present invention provides a pharmaceutical composition comprising novel compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides to novel antimicrobial compounds based on Schiff bases. These compounds have good antimicrobial properties. In particular, the present invention provides metal complex of Schiff base ligand. These ligands have donor atoms such as nitrogen, oxygen, and sulphur which make them compatible with the biological systems.
In one embodiment, the present invention provides novel metal-ligand complex compound of formula (I).

Formula I
Wherein M is selected from Titanium and Zirconium and X is selected from Chlorine and Bromine.

In one embodiment, the compounds of the present invention form a bidentate ligand with a metal. This ability of the compounds to combine with a variety of metal ions, in particular, transition metals, allows them to generate stable metal complexes. Since the metal complexes are stable, they are suitable for use in various applications such as antimicrobial applications. Further since the ligands are bidentate ligands, the compound has metal: ligand ratio of 1:2.

The metal ion M is a transition metal selected from Titanium and Zirconium. In a preferred embodiment, the metal is Titanium. Further the halogen X, in a preferred embodiment is Bromine.

In a preferred embodiment, the present invention provides a novel metal- ligand complex compounds of formula (I) wherein the compound is (Z)-2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide. The said compound is represented by formula II

Formula II
In a preferred embodiment the present invention provides the compounds as below:

Compound 1

Compound 2

In one embodiment, the present invention also provides a process for preparing compound of formula I, said process comprising:
(a) Treating ethyl oxybutanoate with benene 1,2 diamine in the presence of a solvent to obtain 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one
(b) Treating 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one with a chlorinating agent and a base to obtain 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine
(c) Treating 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine with 4 hydroxyacetophenone to obtain 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one,
(d) Treating 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one with thiosemicarbazide to obtain 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide
(e) Treating 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide with a metal salt to obtain the metal complex compound of formula I.

The solvent suitable for use at step (a) is selected from benzene, toluene, hexane, xylene water, methanol, ethanol, ethyl acetate and ether. In a preferred embodiment the solvent is Xylene.
The chlorinating agent suitable for use at step (b) of the in selected from Oxalyl chloride, Phosphorus oxychloride, Phosphorus pentachloride, Phosphorus trichloride and Thionyl chloride. In a preferred embodiment the chlorinating agent is Phosphorus oxychloride
The base suitable for use at step (b) is selected from benzyldimethylamine, pyridine, and imidazole, 4 dimethyl aminopyridine, methylpyridine, Aniline, trimethyl aniline, N, N dimethyl aniline. In a preferred embodiment the base is N, N dimethyl aniline.
Further, the metal salt is Bromide or Chloride of transition metal selected from Titanium and Zirconium. In a preferred embodiment, the metal salt is Titanium tetrabromide or Titanium (IV) Bromide.
The process of the present invention is simple and easily scalable. Further, the compounds synthesized by the above process are obtained in high yield and purity.
The preferred embodiment of the process of the presented invention is shown below in scheme 1

Scheme 1
The compounds of the present invention are effective against a variety of Gram-positive bacteria, Gram-negative bacteria and fungus. In one embodiment, compounds of the present invention are effective against S. aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans, Aspergillus fumigatus and Mycobacterium tuberculosis. The compounds of the present invention are also effective against the drug-resistant strains of these microbes.
Due to the distinctive structural attributes of the ligand, coupled with the influence of the metal ion, the compounds of the present invention have dual advantages. (a) They are themselves effective against variety of pathogenic microbes. (b) Due to their structural properties, they can also serve as building blocks for the development of other novel drugs.
In another embodiment, the present invention provides a pharmaceutical composition comprising the compounds of formula I. In a preferred embodiment, the pharmaceutical composition of the present invention is useful for the treatment of tuberculosis.

Examples: The compounds of the present invention i.e compound 1 (TiCl4 thio), and compound 2 (TiBr4Thio), were tested for their activity against various microbes. The compounds were dissolved in DMSO for required concentration(100mg/ml). All the MGIT tubes were labeled and 0.8 ml supplement was added to each tube. 1st tube was then kept aside and compounds 100 µl from the stock of 100 mg / ml were added to the respective tubes. Tubes were mixed properly and kept aside. 1:100 dilution of DST inoculum (M. tuberculosis (C-1565) was prepared for the Growth control tube (1st tube) and 1:5 dilution of DST inoculum (M. tuberculosis(C-1565) & M. tuberculosis (MDR) were prepared for tubes. 0.5 ml of 1:100 dilution was added to the 1st tube (Growth control tube).0.5 ml of 1:5 dilution was added to other respective tubes. All tubes were incubated in MGIT-320 instrument at 370C. The results are tabulated as below:

Table 1: Results of E.coli
Sr. No. Compound name Compounds concentration PC NC Zone of inhibition
1. TiCl4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 23mm NZ 18mm
16mm
NZ
NZ
2 TiBr4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 17mm*
13mm*
NZ
NZ

Table 2: Results of of S. aureus
Sr. No. Compound name Compounds concentration PC NC Zone of inhibition
1. TiCl4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 23mm NZ 20mm
18mm
NZ
NZ
2 TiBr4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 23mm
20mm
16mm
NZ

Table 3: Results of MRSA
Sr. No. Compound name Compounds concentration PC NC Zone of inhibition
1. TiCl4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 24mm NZ 17mm
15mm
NZ
NZ
2 TiBr4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 19mm
17mm
13mm
NZ

Table 4: Results of C. Albicans
Sr. No. Compound name Compounds concentration PC NC Zone of inhibition
1. TiCl4 Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 23mm NZ 20mm
13mm
11mm
NZ
2 TiBr4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 22mm
19mm
10mm
NZ

Table 5: Results of A. fumigates
Sr. No. Compound name Compounds concentration PC NC Zone of inhibition
1. TiCl4 Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 23mm NZ 29mm
21mm
NZ
NZ
2 TiBr4Thio 100mg/ml
50mg/ml
5mg/ml
1mg/ml 26mm
23mm
NZ
NZ

Table 6: Results of M. tuberculosis
Tube Number Compound Name Extract Type Concentration used per vial Growth Observed
M. tuberculosis (C-1565) Growth Observed
M. tuberculosis (MDR)
1 Growth / Positive Control Nil Nil YES YES
2 Negative Control 1 (NTC-1) DMSO 100 µl DMSO YES YES
3 Compound C 1
(TiCl4 Thio) NA
100 µl (volume) from the stock of 100 mg/ml YES YES
4 Compound C2
(TiBr4Thio) NA
100 µl (volume) from the stock of 100 mg/ml NO NO

, Claims:We claim

1. Novel metal- ligand complex compound of formula (I).


Formula I
Wherein M is metal selected from Titanium and Zirconium and X is selected from Chlorine and Bromine.

2. The novel compound as claimed in claim 1 wherein the X is Bromine.
3. The novel compounds as claimed in claim 1 wherein M is Titanium.
4. The novel compound as claimed in claim 1 wherein the compound has metal:ligand ratio of 1:2.
5. The novel compound as claimed in claim 1 wherein compound of formula I is (Z)-2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide represented by formula II

6. A process for preparing the novel compound of formula I, said process comprising:

(a) Treating ethyl oxybutanoate with benene 1,2 diamine in the presence of a solvent to obtain 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one
(b) Treating 4-methyl 1,3-dihydro-2H- benzo[b][1,4] diazepin-2-one with a chlorinating agent and a base to obtain 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine
(c) Treating 2-chloro-4-methyl-3H-benzo-[b][1,4] diazepine with 4 hydroxyacetophenone to obtain 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one,
(d) Treating 1-(4-((4-methyl-3H-benzo [b] [1,4]diazepin-2-yl)oxy)phenyl)ethan-1-one with thiosemicarbazide to obtain 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide
(e) Treating 2-(1-(4-((4-methyl-3H-benzo[b][1,4]diazepin-2-yl)oxy) phenyl) ethylidene) -1-carbothioamide with a metal salt to obtain the metal complex compound of formula I.

7. The process as claimed in claim 6, wherein the chlorinating agent is selected from Oxalyl chloride, Phosphorus oxychloride, Phosphorus pentachloride, Phosphorus trichloride and Thionyl chloride.

8. The process as claimed in claim 7, wherein the chlorinating agent is Phosphorus oxychloride.

9. The process as claimed in claim 6, wherein the base is selected from benzyldimethylamine, pyridine, and imidazole , 4 dimethyl aminopyridine, methylpyridine, Aniline, trimethyl aniline, N, N dimethyl aniline.

10. The process as claimed in claim 9, wherein the base is N, N dimethyl aniline.

11. The process as claimed in claim 6, wherein the solvent is selected from benzene, toluene, hexane, xylene water, methanol, ethanol, ethyl acetate and ether.

12. The process as claimed in claim 11, wherein the solvent is xylene.

13. The process as claimed in claim 6, wherein the metal salt is Bromide or chloride of titanium or Zirconium.

14. The process as claimed in claim 13, wherein the metal salt is Titanium tetrabromide or Titanium (IV) Bromide.

Dated this the 10th day of October 2024.