Synthesis, Physico-chemical analysis and Biological

Synthesis, Physico-chemical analysis and Biological Studies of

Potent Mannich Base [(4-Chloro-phenyl)-Morpholin-4-yl-methyl] Thiourea

Dr. S. Farook Basha1* & Dr. M. Syed Ali Padusha2 1&2 PG and Research Department of Chemistry, Jamal Mohamed College (Autonomous)

(Affiliated to Bharathidasan University), Tiruchirappalli – 620020, Tamilnadu. *Corresponding author email: [email protected]

Abstract: In this present study, a new Mannich base, in particular [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea (CMT) was synthesised through Mannich reaction by responding 4-Chlorobenzaldehyde, Morpholine and Thiourea as substrate. The structure of the synthesised compound was portrayed by IR, 1H-NMR, 13C-NMR spectroscopy and Characterisation investigations. Utilizing the above compound as ligand, metal complexes were readied and their structures were built up by basic examinations, IR, UV-obvious spectra, molar conductivity and attractive second investigations. Further, the ligand and the metal complexes were tried for antimicrobial action and atomic docking studies to contemplate the connection of Morpholine subordinates against the receptor Extended Spectrum Beta Lactamase (ESBL) of enzyme action. Antimicrobial investigations uncovered that metal edifices have higher action and found to be more potent than those of the metal salts and ligands. The sub-atomic docking results propose a good hydrogen bond connection among GLN and HIS demonstrates the higher liking of ligand than standard antibiotic. Keywords: Morpholine, Beta Lactamase, Atomic docking.

Introduction:

The Mannich reaction1 is a three-component reaction, which involves the condensation of a compound capable of supplying one or more active hydrogen atoms with an aldehyde, (usually formaldehyde) and an N-H derivative (ammonia, any primary or secondary amine or amide)2 in the presence of an acid to give β-amino carbonyl compounds3-4 and have been utilized as a manufactured device in the arrangement of different helpful specialists like, fluoxetine as energizer operator, ethacrynic corrosive a high roof circle diuretic, benzoquinamide, a high insane specialist, Ranitidine, Triprolidine a H-receptor foe, and Trihexyphenidyl hydrochloride, an antispasmodic5. Mannich bases are physiologically responsive on account of the fundamental capacity rendering the particle dissolvable in watery dissolvable when it is changed into ammonium salt6. In the course of recent decades, Mannich bases of heterocyclic particles have been catching the eye of the manufactured scientific experts for their wide extent of natural exercises running from antibacterial7, anticancer, antiparkinson to anticonvulsant, pain relieving, antispasmodic, against HIV, hostile to malarial just as intermediates in sedate union8. Mannich bases are very important and constructive compounds in organic synthesis, especially their role in biochemistry and natural products is of capital importance. Numerous specialists have contemplated the various uses of Mannich response9, 10. In the improvement of coordination science, the metal buildings of Mannich bases assume a significant job. Mannich bases are of enthusiasm for different regions of use11-15. As of late much intrigue has been paid on the combination and characterisation of progress metal buildings containing a Mannich base because of their wide pharmaceutical properties16-20. Many metal particles are known to assume significant jobs in natural procedures in the human body. Metal particles like zinc (II) and copper (II) particles are the most rich change metals in human body, discovered either at the dynamic destinations or as auxiliary segments of various compounds. These metals and a portion of their edifices have been found to display antimicrobial exercises21-23. The expanded commonness of pathogenic microorganisms with protection from clinically valuable anti-infection agents is a developing danger to general wellbeing. In spite of this dire, the point of mooring is the hunt of the most reasonable positions and directions of the ligands in the Ligand Binding Centre (LBC) of the receptor or protein, just as distinguishing proof of elements that may prompt improvement of the ligand-receptor collaboration. The aftereffect of the re-enactment is adaptation of the ligand, which connects with the protein restricting site in the most ideal manner24.

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Sub-atomic docking is most every now and again utilized technique in Structure-Based Drug Design on account of its capacity to foresee, level of precision and compliance of ligand inside the objective restricting site25. Sub-atomic docking is the key for tranquilize displaying, which permits to give agonist/hostility to the organic objective chose and the most great direction for development of a steady mind boggling and the situation among ligand and target. Heterocyclic science is a significant part of natural science bookkeeping wide scope of organic action26. Furthermore, numerous pyridopyrimidine subsidiaries have an assortment of impacts of compound and natural noteworthiness, for example, antimicrobial, pain relieving, hostile to unfavourably susceptible, antitumor, antihypertensive, antileishmanial, antifolate, calming, antituberculostic, anticonvulsant, diuretic, potassium saving, and against forceful exercises27-29. Docking permits lessening costs and timing due to doing the technique that is like elite organic screening30. Knowing the spatial structure of the objective receptor or catalyst and the spatial structure of the ligand it is conceivable to clarify the system of cooperation between them at the sub-atomic level and figure the quality of restricting proclivity between them31. The proportion of the natural action is such ligand fixation at which the cell reaction is equivalent to a large portion of the most extreme. Thusly, ligands with the most noteworthy proclivity gave will square or initiate the atomic objective in organic examinations best of all32. Partiality of the ligand corresponding to the receptor is surveyed both by geometric measures of surface complementarity of the ligand according to the cavity of the receptor and by physico-compound models. Materials and Methods: The dissolving purposes of the incorporated mixes were resolved utilizing a liquefying point mechanical assembly and are uncorrected. Finishing of the reaction and the virtue of the orchestrated compound were found out by TLC utilizing the dissolvable framework Chloroform and Methanol and the spots were identify utilizing UV-Chamber. The incorporated compound were described utilizing MB 3000 arrangement FT-IR Spectrophotometer by KBr-pellet strategy. 1H-NMR spectra was recorded on AMX-400 NMR spectrophotometer at 400 MHz utilizing DMSO-d6 as the dissolvable and tetra methyl silane (TMS) as an inner norm. The concoction shifts are explained in δ ppm. Combination of the moderate and target mixes was cultivated by the means depicted in the Schemes 1 and 2.

Synthesis of Mannich Base - [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea

10 m moles (1.70 g) of Morpholine were dissolved in a 15 mL of Ethanol in a 100 mL 2 neck round bottom flask equipped with a reflux condenser protected by a calcium chloride drying tube and a quick fit thermometer, then 1.5 g of thiourea and 10 m mole (1.36 g) of 4-Chlorobenzaldehyde were dissolved with constant stirring, to this reaction mixture 0.2 to 0.4 mL HCl were added with cooling on an ice bath. Yellow colour solid separates just after the addition of HCl. The mixtures was stirred for 1-2 hours at room temperature. The reaction mixture was refluxed on a water bath at 90-95˚C for3-4 hours, the reaction mixture was examined by TLC with time to time till completion. The excess of solvent was removed under reduced pressure, the product was washed with water and 95% ethanol respectively.

Scheme – 1 – Synthesis of [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea

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Synthesis of transition metal complexes

A solution of 0.1 M of MCl2 (M=Co, Ni, Cu and Zn) in methanol and 0.2 M of [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea in ethanol were added to a round-bottomed carafe and blended well with utilizing attractive stirrer for two hours. The complex framed was separated, washed with refined water and solidified from total liquor.

NH

S

H2N

N

O

Cl

[(4-Chloro-phenyl)-morpholin-4-yl-methyl]thiourea

+ MCl2

Scheme – 2 – Synthesis of transition metal complexes

Biological activity Antimicrobial tests Invitro antimicrobial exercises of the ligand, edifices and free metal particles were assessed by the plate dissemination strategy against the microorganisms, for example, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Rhizoctonia bataicola. Ampicillin and Amphotericin B were utilized as standard for microorganisms and parasites. The microbial separates were kept up on agar incline at 4˚C. The strains were sub refined on new fitting agar plate in a hatchery for 18 h preceding any microbial test. The supplement agar medium was arranged and disinfected via autoclaving at 121˚C, 15 lbs pressure for 15 min and afterward aseptically emptied the medium into the sterile petri plates and permitted to set the bacterial stock culture and these are cleaned on each petri plates by sterile buds. At that point wells were made by well shaper. The Kirby Bauer Agar (KBA) medium was utilized for the dispersion examines assurance and Nutrient stock was utilized as microbial development medium. This technique was rehashed for each petri plate, at that point the petri plates were brooded at 37˚C for about 24h. After hatching, the plates were watched for the zone of restraint. The impact created by the example was contrasted and the impact delivered by the positive control. Supplement agar (NA) was utilized for the enactment of Bacillus species, while NA alone was utilized for different microscopic organisms. All the antimicrobial tests were observed outwardly and UV-spectrophotometric ally and the analyses were acted in triplicate33.

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Atomic docking

Protein preparation34

Auto Dock is a set-up of mechanized docking device. It is intended to anticipate how little particles, for example, substrates or medication up-and-comers, tie to a receptor of known 3D structure. The protein recovered from PDB database. The protein structure of Extended-range β-lactamase (PDB ID: 4LEN). All water atoms expelled from all protein structure and included with Kollmann charges was doled out. The vitality limited protein was then spared in PDB design. Utilizing MGLTools-1.4.6 nonpolar hydrogens were blended, Auto Dock molecule type AD4 and Gasteiger charges were doled out lastly spared in protein.pdbqt design.

Ligand preparation

Structure of ligands were drawn utilizing Chem Sketch, enhanced with 3D-geometry and the two-dimensional structures of manufactured were changed over into 3-D structure utilizing the open Babel design atom converter and spared in PDB position for Auto Dock similarity. MGLTools-1.4.6. The Scripps Research Institute was utilized to change over ligand.pdb records to ligand.pdbqt documents.

Docking protocol-MGL tools35

Framework boundary documents (protein.gpf) and docking boundary records (ligand.dpf) have composed utilizing MGLTools-1.4.6. Receptor networks were produced utilizing 80x80x60 framework focuses in xyz with lattice separating of 0.375 Å. Framework box was focused co solidified ligand map types were created utilizing autogrid4. Docking of macromolecule was performed utilizing an experimental free vitality capacity and Lamarckian Genetic Algorithm, with an underlying populace of 250 arbitrarily positioned people, a greatest number of 106 vitality assessments, a transformation pace of 0.02, and a hybrid pace of 0.80. One hundred autonomous docking runs were performed for every ligand. Results contrasting by 2.0 Å in positional root-mean square deviation (RMSD) were grouped together and spoken to by the outcome with the greatest free vitality of authoritative.

Docking protocol-Hex tools36

The atomic docking between the objective receptor and ligand was performed by Hex device. This apparatus is for intelligent docking and can ready to run in any working framework. There are propelled forms in this instrument and it gives the vitality esteems to all the models. The model can imagine in any structures with docked boundaries. The structure for the ligand CMT can be imagined in the phenol watcher and docked with the structure of Ebola infection and the objective receptor for malignancy. The ligand structure was drawn by Chemsketch and exposed to docking. Both the structures were docked and indicated vitality esteems, for example, E-max, E-min, E-shape, and E-complete. These qualities were determined. The Net accuses of number of directions were likewise determined. At long last, the outcomes were looked at dependent on the docking boundaries.

Results and Discussion

Chemistry

The Mannich base was synthesized by using the method described in earlier literature. All the compounds were obtained in good quantities. The completion of the reaction was confirmed by TLC. The melting point of the synthesized compounds was measured by using open capillary tube method. All the synthesized compounds gave satisfactory IR, 1H-NMR and 13C-NMR spectra were consistent with the assigned structures. Synthesis procedure of the Mannich base and the metal complex was outlined in Schemes 1 and 2. The physicochemical data of the compounds are presented in Table – 1.

Table – 1 – Physicochemical data

Compounds Molecular Formula

Melting Point

Elemental Analysis – Percentage Calculated (Found) Molar

Conductance (Ω-1 cm2

mol-1 in 10-3 C H N O S Cl

CMT C12H16ClN3OS 172˚C 50.43 (50.11)

5.64 (5.26)

14.70 (13.56)

5.60 (5.10)

11.22 (10.54)

12.41 (12.25)

--

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Co(II)-CMT [C12H16ClN3OSCo]Cl2 176 ˚C 49.41

(48.20) 5.52

(5.21) 13.52

(12.58) 5.82

(5.45) 11.15

(10.59) 12.35

(12.16) 192

Ni(II)-CMT [C12H16ClN3OSNi]Cl2 179 ˚C 49.33

(47.89) 5.21

(5.10) 13.28

(11.56) 5.80

(5.65) 11.10 (11.5)

12.29 (12.16)

181

Cu(II)-CMT [C12H16ClN3OSCu]Cl2

183 ˚C 49.25 (48.56)

5.28 (5.16)

12.28 (11.56)

5.89 (5.72)

10.9 (10.2)

12.15 (12.10)

184

Zn(II)-CMT [C12H16ClN3OSZn]Cl2 186 ˚C 48.55

(47.26) 5.19

(5.12) 12.17

(11.56) 5.55

(5.46) 10.54

(10.21) 12.10 (12.2)

156

Physical and spectral data of the synthesized compound FTIR Spectra

Figure – 1 – FTIR spectra of [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea

The ligand and its metal buildings were broke down by IR spectroscopy. The outcomes were utilized to analyse ionic and covalent bonds related with coordination mixes. IR spectroscopy proposes that when metal particle consolidates with the ligand to frame complex, its vibrational spectra expected to change. The striking highlights of IR range of a ligand and edifices are given in the Table – 2.

Table – 2 - IR SPECTRAL DATA OF (MORPHOLIN-4-YL-PHENYL-METHYL)-THIOUREA

FUNCTIONAL GROUP FREQUENCY cm -1

N - H Stretching 3353

Aromatic C-H stretching 2340

C-H aliphatic stretching 1975

C-N stretching 1446

C-Cl 761

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The expansive band shows up at 3353cm-1 is relegated to extending of amide NH. The expansive band in the region 2340cm-1 is because of fragrant C-H extending. The band showing up at 1975cm-1 is allotted to (C-H) aliphatic extending. The band showing up at 1446cm-1 is appointed to C-N extending. The band showing up at 761cm-1 is doled out to C-Cl extending. 1H- NMR Spectra

Figure – 2 – 1H-NMR spectra of [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea

Table – 3 – 1H-NMR SPECTRAL DATA OF (MORPHOLIN-4-YL-PHENYL-METHYL)-THIOUREA

GROUP ASSIGNMENT CHEMICAL SHIFT (δ ppm)

NH Proton (1H,s) 2.2

Phenyl Protons (4H,m) 7.9-7.7

Aliphatic CH 4.9

Morpholine ring Protons (m) 3.4-3.3

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The compound shows a singlet δ 2.2 which is due to the NH proton (1H). The compound shows multiples at δ 7.9-7.7ppm, are assigned to the aromatic protons. The Morpholine protons are in the

range

of δ

3.4-3.3ppm. The singlet δ 4.9ppm which is due to the aliphatic CH.

13C-NMR spectra Figure – 3 – 13C-NMR spectra of [(4-Chloro-phenyl)-Morpholin-4-yl-methyl]Thiourea

Table – 3 – 13C-NMR SPECTRAL DATA OF (MORPHOLIN-4-YL-PHENYL-METHYL)-THIOUREA

GROUP ASSIGNMENT CHEMICAL SHIFT (δ ppm)

Phenyl Carbons 132.8-129.2

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The

phenyl ring shows its range 132.8-129.2 (4C) is due to the presence of aromatic carbons. The compound shows at 85.9δ which is due to aliphatic carbon group. The compound shows at 54.4δ (4C) which is due Morpholine ring carbons.

Antimicrobial Studies

Table – 4 – Antimicrobial activity of the ligand and its metal complexes

Complex Inhibition zone(mm)

Staphylococcus aureus

Escherichia Coli Pseudomonas

aeruginosa Bacillus subtilis

CMT 11 12 12 10 Co-CMT 19 16 14 15

Ni-CMT 12 11 10 11

Cu-CMT 14 13 15 14

Zn-CMT 13 12 10 12

Ampicillin 11 11 11 10 DMSO -- -- -- --

Metal Salt 13 15 14 11

The results of the antimicrobial activity of the CMT and its complexes are presented in Table 3. From the table, it is observed that the metal complexes are more active than the free ligand and their standards. The increase in antimicrobial activity is due to faster diffusion of metal complexes as a whole through the combined activity of the metal and the ligand.

Table – 5 – Atomic Docking data of metal ligand with Extended Spectrum Beta Lactamase

S.No. Compound name

Docking Score Inhibitory Concentration

H-bond interaction

Distance

1 Compound Cu

-5.16 4.1 SER237 N-

H…O

2.125

2 Compound Co

-5.6 2.1

GLN192 N-H…O

HIS197 N-H…O

2.146 2.111

3 Ciprofloxacin

-3.9 364

SER235 N-H…O

SER130 N-H…O

1.958 1.793

Query Molecule

Aliphatic Carbon 85.9

Morpholine Ring Carbons 54.4

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Figure – 4 – Target Site prediction against Homo Sapiens

Figure – 5 - Extended Spectrum Beta Lactamase with CMT-Cu (II) Docking study of Cu (II) complex of CMT with ESBL

Fig. 5 reveals that the amino corrosive build-ups SER237 was engaged with cooperation’s with compound Cu (II) the dynamic site of ESBL. The amino corrosive deposits SER237 was engaged with cooperation’s with compound Cu (II) the dynamic site of ESBL. The length of hydrogen bond shaped 2.125Å. The IC50 estimations of this compound have 4.1 μm and low docking score (- 5.16). Docking score of the complexed inhibitor was seen as - 5.16, with RMSD of 0.486. The sub-atomic segments incorporate qualities and quality.items, yet additionally other concoction substances in living cells37.

NH

S

H2N

N

O

Cl

[(4-Chloro-phenyl)-morpholin-4-yl-methyl]thiourea

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Figure –6 –Extended Spectrum Beta Lactamase with CMT-Co (II)

Docking study of Co (II) complex of CMT with ESBL

Fig. 6. Reveals that the amino corrosive deposits GLN192 and HIS192 were associated with cooperation’s with compound Co (II) the dynamic site of ESBL. The amino corrosive build-ups GLN192 and HIS192 were associated with cooperation’s with compound Co (II) the dynamic site of ESBL. From the table it was noticed that the length of hydrogen bond framed 2.111å and 2.146Å. The IC50 estimations of this compound have 2.1(μm) and low docking score (- 5.6). The cooperation of tried metal particles with natural ligands shows better antibacterial movement contrasted with free ligand a decision for new medications with Beta Lactam delivering pathogenic microbes. Studies show that metal buildings with copper particles infiltrate all the more effectively through the bacterial cell divider, due to denature protein with sulphydrile bunch [22] and pulverizing the bacterial cell divider.

Conclusion

The ligand, CMT and its metal complexes have been combined and described by essential examination, IR, 1H-NMR, 13C-NMR and trademark examinations. Antimicrobial screening of ligand and the metal complexes demonstrated their magnificent action. The zone of hindrance of metal complexes are similarly high than the free ligand. The remedial guarantee of the examined metal (II) complexes were found to show higher antimicrobial movement than the ligand. Restricting energies of the ESBL protein-ligand (medicate) associations are critical to depict how fit the medication ties to the objective macromolecule. We have endeavoured to find ESBL inhibitors by performing sub-atomic docking and sub-atomic elements concentrates on ESBL with Morpholine subordinate. Our docking re-enactment brought about a nearby objective protein structure, which underpins our discoveries. The mixes Co (II) and compound Cu (II) were profoundly interfacing with ESBL. It is imperative to that progressively trial contemplates are expected to discover the connection among MIC and collaboration vitality.

ACKNOWLEDGEMENT

We might want to thank the Management Committee and Principal of Jamal Mohamed College, Trichy for giving every single specialized part of this research investigation.

CONFLICT OF INTEREST

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The authors don’t have any conflict of interest.

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