Molecular Docking Studies as Antidepressant Agents, Synthetic Techniques, Antimicrobial Screening of Azetidine-2-One Derivatives- A Review

S. Ramachandran, Vimeshya. N, K. Yokeshwaran, Binoy Varghese Cheriyan,

M. Vijey Aanandhi

Department of Pharmaceutical Analysis, Vels Institute of Science Technology and Advanced Studies, Pallavaram, Chennai.

*Corresponding Author E-mail: ramachandrans.sps@velsuniv.ac.in

ABSTRACT:

Azetidine-2-one derivatives were reported to possess antibacterial, antifungal and antidepressant activity.Pyridine derivatives were reported to possess antimicrobial activities Four-membered nitrogen heterocycles such as β-lactam and azetidines are useful substrates in organic chemistry for the design and preparation of biologically active compounds. Azetidine-2-one derivatives were synthesized by the reaction of the Schiff base with 2-chloroacetic acid. The different substituted azetidine derivates were synthesized followed by cyclizations by C-N bond formation and by the C-C bond formation, the amine-catalyzed cycloaddition of allenoates and imines, photocycloadditions of imines and alkenes, ring contraction and expansion rearrangements, and reduction of azetidine-2-ones(β-lactams). Synthesized compounds were evaluated for their Anti-bacterial activity against Staphylococcus aureus and Escherichia coli. The synthesized structure was established based on element analysis, IR, 1H NMR, and Mass spectral data. This indicates that new azetidine derivates can be effectively synthesized by the method mentioned in this study. Azetidine is a saturated heterocyclic organic compound containing three carbon atoms and one nitrogen atom. Indole bearing azetidine derivatives are exhibiting various biological activities. Indole bearing azetidine derivatives act as an antidepressant agent has been relatively less explored. To get intermolecular interactions, the molecular docking studies are performed at the active site of the MAO-A enzyme. This study is to generate a new molecular template by linking two pharmacophores (indole and azetidine), which are likely to exhibit antidepressant-like action in animal models. The derivatives were synthesized by spectrometric methods. Molecular docking studies of the synthesized derivatives with MAO-A enzyme were carried on by using the k-nearest neighbor genetic algorithm method. All the structures were assigned based on IR, 1H NMR, mass spectra and elemental analysis. Molecular docking studies included with pharmacological evaluation for potent compounds exhibiting dock score. These compounds may have enough potential to be developed as an antidepressant agent. It can be studied for their structural -activity relationship (SAR) studies and developed into potential molecules lead. It can make a great impact on the development of MAO-A inhibitors.

KEYWORDS: Indole, Azetidinone, Antidepressant activity, Docking study, azetidine-2-one, Schiff base, antimicrobial, isoniazid.

INTRODUCTION:

Azetidinone derivatives were reported to possess antibacterial^1-2, antifungal³. Pyridine derivatives were reported to possess antimicrobialactivities Four -membered nitrogen-containing heterocyclic such as 2-azetidine are useful substrates in organic chemistry for the design and preparation of biologically active compounds by adequate fictionalization in the different positions of the ring. Azetidinones are a part of the antibiotic structure, which possesses interesting biological activities. A large number of 3-chloromonocyclic ß-lactam rings having substitution at positions 1 and 4 exhibits powerful antibacterial, antifungal, pharmaceutical, anti-inflammatory, herbicidal, hypocholesterolemic, anticonvulsant, anti-tubercular, anticancer and antibiotic activities. They also function as enzyme inhibitors and are effective against the CNS. These are carbonyl derivatives of azetidine containing carbonyl group at position -2. They are also known as 2-azetidine or more commonly β-lactams. Schiff base is used as substrates in the preparation of industrially and biologically active compounds via ring closure, cycloaddition and replacement reactions. The structures of the various synthesized compounds were assigned based on IR, 1H NMR spectral data and elemental analysis. These compounds were also screened for their antimicrobial activity. The research was aimed to explore an efficient method to synthesize the Schiff base and azetidines.

Depression is a prevalent psychiatric disorder. The WHO predicts that it will be the second leading cause of death by the year 2020 due to complications arising from stress and the cardiovascular system. The depressive condition may be due to a lack of noradrenaline and serotonin. The synthetic drugs used in the treatment of such illness act by affecting the system of biogenic amines of the brain, thus leading to activation of a mechanism that is capable of increasing their concentration in the brain. Monoamine oxidases (MAO) are a family of enzymes in the CNS that catalyzes the oxidation of or inactivation of biogenic amines. MAO inhibitors act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters (noradrenaline and serotonin) and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAOA, and MAOB. MAOA preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAOB preferentially deaminates phenethylamine and certain other trace amines. MAOA inhibitors have been employed in the treatment of depression, anxiety, and mental disorders while MAOB inhibitors could be used in the treatment of Parkinson's disease and Alzheimer's disease. Compounds containing the azetidine nucleus have been reported to possess diverse pharmacological activities. A molecular docking study was performed for the prediction of the binding model of the final derivatives in the target of the MAOA enzyme.

MATERIALS AND METHODS:

All the chemicals used were purchased and were purified by an established method (whenever needed). Various substituted Isoniazid (Schiff base) derivatives were prepared according to the procedure outlined in scheme-1. 2-oxoazetidine derivatives were synthesized by the formation of imines (from 2-chloro acetyl chloride) followed by cycloaddition of ketenes to imines, in the presence of 1:4 Dioxane, in a single-step reaction. Melting points were determined by an open capillary tube method and are uncorrected. The purity of synthesized compounds was checked by TLC plates (Silica Gel G) and visualized by iodine vapor.

The Infrared absorption spectra of the synthesized compounds could be recorded using KBr disc on the FTIR model. 1H NMR and Mass spectroscopical analysis would be performed for assessing the Structure of the compound and the molecular weight of the compound.

All chemical shift values were recorded as d (ppm), coupling constant value J is measured in hertz, the peaks are presented as s (singlet), d (doublet), t (triplet), brs (broad singlet), dd (double doublet), m (multiplet). The purity of compounds was controlled by thin-layer chromatography (silica gel HF254e361, type 60, 0.25 mm; Merck, Darmstadt, Germany). Electrospray ionization mass spectrometry (ESIMS) was recorded at Waters QTOF spectrometer (Waters, Milford, MA, USA).

DIFFERENT METHODS OF SYNTHESISING AZETIDINE-2-ONES:

Ramachandran et al⁴ had synthesized azetidine-2-one derivatives and the antimicrobial activity of the synthesized compounds was performed by cut plate method and the synthesized compounds showed good activity against the gram-positive and gram-negative organisms.

N.M. Andurker⁷ et al reported Schiff base converted into 4-thiazolidinone and 2-azetidinone by the action of mercaptoacetic acid and chloroacetylchloride respectively. The synthesized compounds showed antibacterial activity against Bacillus subtillis, Salmonella dysentrea, and Salmonella typhi.

ANTIMICROBIAL ACTIVITY:

All the synthesized compounds were evaluated for their in vitro antimicrobial activity against gram-positive bacteria Staphylococcus aureus, the gram-negative bacteria Escherichia coli in nutrient agar media, The zone of inhibition values were determined and compared with well known(standard) antibacterial (Ofloxacin), antifungal (Ketoconazole) and antituberculosis (Isoniazid) drugs.

MOLECULAR DOCKING STUDY:

For docking purposes, the three-dimensional structure of MAOA (protein data bank, PDB code 2BXS) was obtained from RCSB PDB. The receptor molecule was refined and validated using the module on the MDS. The Life MDS suite uses a k-nearest neighbor genetic algorithm (KNNGA) method for molecular docking ^8,9,10. The ligands that were already present within the receptor in bound form were removed to allow for docking protocol. All the ligands were prepared and docked for this study in flexible docking mode and atoms located within a range of 5.0 Å from the amino acid residues were selected in the active site. Standard drug fluoxetine was also included in the series of compounds understudy to make comparisons concerning in silico analysis. The active sites of the MAOA (PDB code 2BXS) were identified which was comprised ALA44, ALA68, ARG45, ARG51, GLU43, GLY20, GLY22, GLY50, GLY66, HIS242, ILE19, ILE2, ILE273, LEU42, PRO243, SER24, TRP397, TYR69 and TYR402 that were the interacting residues.^11,12,13,14

Docking studies with these derivatives with MAOA enzyme (PDB code 2BXS). The Life MDS suite uses a k-nearest neighbor genetic algorithm (KNNGA) method for molecular docking. Before carrying out docking the MAOA enzyme at the site of action. The docking studies with interactions like hydrogen bonding hydrophobic interaction and the Van der Waals forces interactions were considered. The compound used that it binds to the active site of MAOA enzyme by forming a hydrogen bond with GLU446A [bond length: 1.981 Å; In the above Figure. Hydrophobic interactions were found to be mostly between GLY 22A, ILE 23A, SER 24A, GLY 434A, ALA 448A and FAD 600 A with the bond length between 2.0 and 4.709 Å Figure. It also formed Van der Wall's interaction with enzyme amino acids having a bond length between 2.0 and 3.9 Å. Compound prominently displayed that it binds to the active site of the MAOA enzyme by forming a hydrogen bond with GLY 66A [bond length: 2.551. Hydrophobic interactions were found to be mostly among ILE 23A, ARG 51A, THR 52A, MET 445A, ALA 448A, FAD 600A with bond lengths between 4.26 and 4.93 Å. It also formed Van der Wall's interaction with enzyme amino acids having a bond length between 2.81 and 3.85 Å [F Apart from the hydrogen and hydrophobic bonding, a crucial π-π interaction with TRP 397A with bond length 3.511.^15,16,17

RESULTS AND DISCUSSION:

The yield of synthesized compounds was found to be satisfactory. The purity of synthesized compounds and completion of reactions were checked by TLC on silica Gel G plates in the solvent system methyl chloride: methanol (8:2 v/v) and visualized spots in iodine vapor. Proposed structures were confirmed by Spectral and microanalysis data. The presence of various functional groups and heteroatom were supported by the IR and Mass spectral data. Further elemental analysis data were also found in agreement with calculated values from proposed structures.

Antimicrobial screening data of synthesized compounds would be performed, against gram-positive and gram-negative bacteria, as compared to the reference drug. The effectivity of the synthesized compounds would be assessed by the zone of inhibition. From the above study, it is shown that azetidinone showed good docking property again the MAO-A enzyme.

CONCLUSION:

In summary, this research work was oriented towards the finding of newer Azetidine derivatives with antimicrobial activities. The different substituted azetidine derivatives were synthesized followed by cyclization reaction. The newly synthesized azetidine derivatives were evaluated for their antimicrobial, anti-depressant activity by docking study. Process optimization, clinical safety and dosage form development of new azetidine derivative by this scheme are highly desirable. It is therefore concluded that the present research is useful to explore many simple and easy means of synthetic schemes in the processing of complex and potent chemicals as well as therapeutics moieties.

Molecular docking studies are with the pharmacological evaluation with potent compounds exhibiting a docking score of 2.8474. It also suggested that the high lipophilic group in ring C can experience an extra hydrophobic binding region that can contribute a significant pharmacological activity toward the CNS depressant activity. It can be stated that these compounds can be further studied for their structure-activity relationship (SAR) studies and developed into potential lead molecules. So our research can make a great impact on those medicinal chemists who work on the development of MAOA inhibitors.

ACKNOWLEDGMENT:

The authors are thankful to the Vels Institute of Science Technology and advanced studies and management for providing us the necessary facilities and also utility of the library facility online journal facilities and constant encouragement.

REFERENCE:

1. G. S. Singh, B. J. Molotsi; Synthesis of 2-azetidine from 2-diazo-1, 2-diarylethanones and N-(2-vinylidene) imines as possible antimicrobial agents Il Farmaco., 2005; 60: 727-730.

2. V. P. M. Rahman, S. Mukhtar, W. H. Ansari, G. Lemiere; Synthesis, stereochemistry and biological activity of some novel long alkyl chain substituted thiazolidine-4-ones and thiazan-4-one from 10-undecenoic acid hydrazide Eur. J. Med. Chem., 2005; 40: 173-184.

3. D. S. Mehta, V. H. Shah; Indian. J. Heterocyc. Chem., 2001; 11: 139-144.

4. S. Ramachandran, S. Nandini, M. Noorul Hudha, Omer Abdul Gader, Otieno Winston Churchill, M. Rajasheik Nasrudeen Shah, Dr. R. Sundhararajan Synthesis, Characterization, Antimicrobial evaluation of Azetidinone derivative in World Journal of Pharmacy and Pharmaceutical Sciences,2014,3(6),1466-1470.

5. Ravindra Kumar, Abha Shuk lab, and D.S. Tyagi. Synthesis of Bioactive Azetidinones of 4-Phenyl-1, 3-thiazole-2-amine. Chem Sci Trans., 2013:2(4); 1518-1522.

6. Havaldar FH, Bhise SS, Burudkar SM. Convenient synthesis and biological activity of 2-azetidinones and 4-thiazolidinediones. Indian J heterocyclic chem.2005; 14: 297-300.

7. N.M. Tendulkar, R.P. Pawar and Y.B. Vibhute, Synthesis and antibacterial activity of some new anils, 4-thiazolidinediones, and 2-azetidinones. Orient.J.Chem.2003:19 ;685-688.

8. Schechter LE, Ring RH, Beyer CE. Innovative approaches for the development of antidepressant drugs: current and future strategies. Neuro therapeutics. 2005;2(4):590–11

9. Tran PV, Bymaster FP, McNamara RK, Potter WZ. Dual monoamine modulation for improved treatment of the major depressive disorder. J. Clin. Psychopharmacol. 2003;23(1):78–86.

10. Tipton KF, Boyce S, O’Sullivan J, Davey GP, Healy J. Monoamine oxidases: certainties and uncertainties. Curr. Med. Chem. 2004;11(15):1965-82.

11. Edmondson DE, Mattevi A, Binda C, Li M, Hubálek F. Structure and mechanism of monoamine oxidase. Curr. Med. Chem. 2004;11(15):1983–93.

12. Rudorfer MV, Potter WZ. Antidepressants: a comparative review of the clinical pharmacology and therapeutic use of the “newer” verses the “older” drugs. Drugs. 1989; 37:713–38.

13. Wouters J. Structural aspects of monoamine oxidase and its reversible inhibition. Curr. Med. Chem. 1998; 5(2):137-62.

14. Manna K, Aggarwal Y. Microwave-assisted synthesis of new indophenazine 1, 3, 5-trisubstituted pyrazoline derivatives of benzofuran and their antimicrobial activity. Bioorg. Med. Chem. Lett. 2009;19(10):2688-92.

15. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer. 2004;4: 253-65.

16. Shibinskya MO, Lyakhov SA, Mazeppa AV, Andronati SA. Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of 6-(2-aminomethyl)-6H-indolo [2, 3-b] quinoxalines. Eur. J. Med. Chem. 2010;45(3):1237-1243.

17. Palluotto F, Carotti A, Cassini G, Campagna F, Genchi G, Structure-activity relationship of 2-aryl-2, 5 dihydro pyridazine [4,3-b] indol-3-(3H)-ones at the benzodiazepine receptor. Bioorg. Med. Chem. 1996;4(12):2091-04.

Received on 17.12.2019 Modified on 17.02.2020

Research J. Pharm. and Tech. 2020; 13(11):5524-5528.

DOI: 10.5958/0974-360X.2020.00964.6