Browsing by Author "Das, Rajesh Kumar"

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Open Access
Investigation on salt-solution and solution-solution properties by physico-chemical techniques
(University of North Bengal, 2010) Das, Rajesh Kumar; Roy, Mahendra Nath
Open Access
Polydentate ligand based metal complexes for oxidase activity
(University of North Bengal, 2023) Sahin Reja; Das, Rajesh Kumar
Polydentate ligands have been widely studied due to their ability to form stable and efficient metal complexes. In recent years, there has been growing interest in the use of these metal complexes as catalysts for various chemical reactions, including oxidase activity. Oxidases are enzymes that play a crucial role in biological processes such as cellular respiration and metabolism. The development of synthetic metal complexes with oxidase-like activity has the potential to provide alternative catalysts for these important processes. In this abstract, we discuss the design and synthesis of polydentate ligand based metal complexes for oxidase activity. We focus on the use of N, O-chelating ligands that have been shown to form stable and efficient metal complexes. The metal complexes are characterized using various spectroscopic techniques, and their oxidase activity is evaluated using a variety of assays. We also explore the mechanistic aspects of the oxidase activity of these metal complexes and compare their activity to that of natural oxidase enzymes. Overall, the results demonstrate the potential of polydentate ligand based metal complexes as efficient catalysts for oxidase activity. These complexes may provide a viable alternative to natural oxidase enzymes, and their development could lead to the development of new therapeutic agents and industrial catalysts. Polydentate ligands are molecules that possess multiple donor atoms capable of bonding with a central metal ion. Metal complexes of polydentate ligands have gained significant interest in recent years for their potential applications in various fields, including catalysis, drug design, and biotechnology. In particular, metal complexes of polydentate ligands have been shown to exhibit exceptional oxidase activity, making them an attractive candidate for various oxidation-based reactions. Oxidation is an essential process in biological systems, and the use of metal complexes of polydentate ligands in catalyzing oxidation reactions is a promising area of research. The oxidase activity of these metal complexes can be attributed to the presence of redox-active metal centers, which can donate or accept electrons during the oxidation process. The polydentate ligands stabilize the metal ion and enhance its reactivity, resulting in increased catalytic activity. The catalytic activity of polydentate ligand-based metal complexes for oxidase activity is dependent on several factors, including the types of metal ion, the coordination environment, and the ligand structure. The choice of metal ion plays a significant role in determining the catalytic activity of the complex. Transition metals such as copper, iron, and manganese have been extensively studied for their oxidase activity. These metals possess a variable oxidation state, allowing them to undergo redox reactions during the oxidation process. The coordination environment of the metal ion is another critical factor in determining the oxidase activity of the metal complex. The coordination environment influences the electron transfer properties of the metal ion, which in turn affects the catalytic activity of the complex. Ligands that provide a favorable coordination environment, such as chelating ligands, can enhance the catalytic activity of the complex. The structure of the polydentate ligand also plays a crucial role in determining the catalytic activity of the metal complex. The ligand structure can influence the binding affinity of the ligand for the metal ion, as well as the redox properties of the metal ion. Ligands with multiple donor atoms, such as bidentate and tridentate ligands, have been shown to exhibit excellent catalytic activity due to their ability to stabilize the metal ion. Polydentate ligand-based metal complexes have been shown to exhibit oxidase activity in various reactions, including the oxidation of alcohols, amines, and sulfides. These complexes can also catalyze the oxidation of organic compounds under mild conditions, making them attractive for industrial applications. The use of polydentate ligand-based metal complexes in the oxidation of biomolecules, such as DNA and proteins, is an exciting area of research that holds promise for various biotechnological applications. In conclusion, polydentate ligand-based metal complexes have shown exceptional oxidase activity, making them a promising candidate for various oxidation-based reactions. The catalytic activity of these complexes is dependent on several factors, including the choice of metal ion, the coordination environment, and the ligand structure. The use of these complexes in industrial applications and biotechnology holds significant promise and is an exciting area of research for the future. CHAPTER I Chapter I is an introductory one that describes polydentate ligand based metal complexes as efficient catalysts for oxidase activity and their applications in various fields as well as single crystals, their classification and methods of growth. Object and application of the present research work has also been outlined in this chapter. A brief description of the advantages of different type of technique of crystal growth was described. CHAPTER II Chapter II involves the experimental section briefly describing the chemicals and materials used in completing this research. This chapter also describes the novelty behind choice of organic linkers/ligands used in the works embodied in this thesis. This chapter also contains details of the physico-chemical and spectroscopic techniques, viz., single crystal, FTIR spectroscopy, NMR, and EPR, etc., used for the physicochemical characterization of the synthesized complexes. This chapter also describes the theoretical characterization (DFT, etc) of the hybrid complexes. CHAPTER III 2-(3-(Dimethylamino)propyl)isoindoline-1,3-dione (DAPID) has been synthesized and utilized to produce 3-(1,3-dioxoisoindolin-2-yl)-N,N-dimethyl propan-1-aminium perchlorate (DIDAP). Both DAPID and DIDAP were characterized using different spectroscopic techniques. Structure of the DIDAP has been determined using single crystal X-ray diffraction technique. DIDAP found to self assemble in a helical motif in its supramolecular structure with the aid of different hydrogen bonding, Cg···Cg and short interatomic contacts in the solid state. The compound DIDAP exhibited anticancer activity against the human hepatomas cell line (Hep G2) and the activity was further complemented by performing docking study. In addition, the computational studies have also been performed to examine the chemical reactivity of the compound. Shape index and Curvedness surfaces indicated -stacking with different features in opposed sides of the molecule. Fingerprint plot showed C···C contacts with similar contributions to the crystal packing in comparison with those associated to hydrogen bonds. Enrichment ratios for H···H, O···H and C···C contacts revealed a high propensity to form in the crystal. CHAPTER IV N1, N4- Bis(3-(dimethylamino)propyl)succinamide (DAPS) has been synthesized and utilized to produce 3,3'-[succinylbis(diazaneyl)]bis(N,N,N-trimethylpropan-1-ammonium) perchlorate (SAPAP). Both DAPS and SAPAP were characterized using different spectroscopic techniques. Structure of the SAPAP has been determined using single crystal X-ray diffraction technique. The compound SAPAP had excellent anticancer activity against the human colon carcinoma cell line (HT-29), proposing them as a suitable candidate for future anticancer therapies. Docking, Molecular dynamics simulation, pharmacokinetic predictions and ELISA were also employed to evaluate the inhibitory action of the synthesized compound against the said cancer cell line HT-29. CHAPTER V Keeping in mind the importance of oxidase activity it includes a versatile bioinspired metallocatalyst [Cu2L2(OAc)4] (L = 2-(3-(dimethylamino)propyl)isoindoline-1,3-dione), which has been synthesized and characterized as reported. To the best of our knowledge, a very few articles of paddlewheel type complexes have reported behave as catechol oxidase activity and phenoxazinone synthase activity. The EPR, CV, and ESI Mass analyses collectively support that the complex exhibits such activity via oxygen dependant enzymatic radical pathway. Furthermore, these activities are observed under fully aerobic conditions in which 3,5-di-tert-butylcatechol (3,5-DTBC) and 2-amino phenol (2-AP) are used as model substrates. Michaelis-Menten analysis derived from the pseudo first-order reaction kinetics established that this complex shows prominent catalytic activity towards 3,5- DTBC and 2-AP (Kcat 12.0726×103 h-1 and 6.6654×103 h-1). Molecular electrostatic potential (MEP) diagrams and density functional theory (DFT) reveals the charge density region within the complex while growth inhibition (GI50) and molecular docking study exposes substantial dose dependent anti-leukemic activity against Hep-G2 cell line. Moreover, promising anti-bacterial property was also detected on multi-drug resistant E. coli and B. cereus bacteria. CHAPTER VI In this chapter a promising bioinspired metallocatalyst [Cu(L1)2(L2)] (L1 = P-hydroxybenzoic acid, L2= N1,N1-dimethylpropane-1,3-diamine) has been produced and characterized in accordance with reports.. In the octahedron arrangement around the copper ion, the elongation along one axial direction and one equatorial direction results in a distorted geometry. Molecular assembly shows both inter and intra molecular H-bonding along with C-H---π interactions evident from the Hirshfeld surface analysis. The fingerprint plot discloses the relative contribution of percentage of intermolecular contacts (H⋯H, C⋯H and O⋯H) in the complex. To the best of our knowledge, no one has reported catechol oxidase activity and phenoxazinone synthase activity of Cu(II) complexes with P-hydroxy benzoic acid and propyl amine ligands so far. The EPR, CV, and UV analyses collectively support that the complex exhibits such activity via oxygen dependant enzymatic radical pathway. Furthermore, these activities are observed under fully aerobic conditions in which 3,5-di-tert-butylcatechol (3,5-DTBC) and 2-amino phenol (2-AP) are used as model substrates. Michaelis-Menten analysis derived from the pseudo first-order reaction kinetics established that this complex shows extremely high catalytic activity towards 3,5- DTBC and 2-AP (Kcat 1.729×105 h-1 and 0.260×105 h-1). The suggested mechanism has been supported by UV spectra data in which formation of hydrogen peroxide by observing the appearance of spectral band at λmax 353 nm indicates the active participation of molecular oxygen in the catalytic process. CHAPTER VII Future research in the field of polydentate ligand-based metal complexes with a focus on enhancing oxidase activity holds significant promise. These studies may lead to the development of novel ligands, versatile multifunctional complexes, and applications spanning biotechnology, medicine, energy conversion, and industrial processes, offering innovative solutions with broad-reaching implications for various fields.
Open Access
Virtual screening, molecular docking studies admet properties dencity functional theory and 2D-QSar modeling to design potential inhibitors
(University of North Bengal, 2023) Sarkar, Subhajit; Das, Rajesh Kumar
Conventional drug design processes use trial and error methods for screening natural and synthetic compounds. It costs millions of dollars and very long time approximately 10-15 years. To meet these severe challenges nowadays pharmaceutical companies rely very much on computer-aided design techniques to discover potential drugs. Throughout the research work, various natural inhibitors that regulate a variety of physiochemical processes in bacteria and human beings have been studied. Derivatives of them have been designed and developed in such a way that they may be used as potent drugs producing no or minimal side effects and overcome the antibiotic resistance property. We hope, in silico drug design processes followed in different studies would save precious time and millions of dollars, leading to novel alternate therapeutics. CHAPTER I Microorganism including bacterium communicates among themselves through a unique mechanism called quorum sensing. The different QS pathways of Gram-negative and Gram-positive bacteria have been discussed elaborately in this chapter. Bacteria develop antibiotic resistance through various mechanisms among them biofilm formation is regulated by quorum sensing. Quorum sensing inhibitors (QSIs) interrupt the expression of virulence factors production and inhibit biofilm formation without killing bacteria or inhibiting bacterial growth. The QSIs are of two types natural and synthetic. It includes a details study of different types of QSIs and inhibition mechanisms. Hamamelitannin (HAM) a phytochemical has the capability to inhibit Staphylococcus aureus agr QS system. Our approach is to modify HAM by incorporating an active functional group for better efficacy. We have followed the same in silico process in another study where the target protein was chosen as heat shock protein 90 rather known as HSP90 and found in all species ranging from bacteria to humans. Over expression of this client protein may lead to several refractory diseases including cancer, inflammation, neurodegeneration, and viral infection. It discussed the various roles and functions of HSP90 in the human body. Besides, we have performed quantitative structure activity relationship (QSAR) analysis in two different cases. Phophodiesterase-4 (PDE4) and lysine-specific demethylase 1 (LSD1) are two key proteins that regulate various physiochemical processes in humans. Over expression of PDE4 may lead to severe diseases including chronic obstructive pulmonary disorder (COPD), and cardiovascular disease whereas unregulated LSD1 may result in tumorigenesis, neurodegenerative disorders, viral infection, diabetes, fibrosis, and various types of cancers including prostate, gastric, breast, lung, and leukemia. Separate studies of QSAR on these two proteins help us to identify best-fitted designed molecules as potent inhibitors of the target proteins. Detailed information on both PDE4 and LSD1 is described here. CHAPTER II The major in silico techniques that are widely popular among researchers are molecular docking, density functional theory (DFT) calculation, molecular docking, molecular dynamics (MD) simulations, and absorption, distribution, metabolism, excretion, toxicity (ADMET) prediction. Collective use of all of the mentioned computer aided techniques is necessary to predict potential QS inhibitors. It includes methodologies of all of the above mentioned techniques in detail. CHAPTER III A set of 26 derivative compounds have been designed by incorporation of different active functional groups at various positions of hamamelitannin (HAM) shown here. All structures were optimized using Gaussian software. Gaussian outputs were used to perform molecular docking with the help of Autodock Vina software. Docking results of HAM with three target proteins of PDB ID 4AE5, 4G4K, and 2FNP exhibited the binding energy value of -6.7, -6.5 and -6.6 kcal/mol respectively. Out of 26 derivatives of HAM, 14 compounds have shown higher binding affinity than that of HAM. The above in silico studies concluded that 14 ligands could be developed as effective inhibitors of S. aureus biofilm formation and considered for in vitro and in vivo analysis. CHAPTER IV It includes the natural product oroidin (ODN) considered a potent inhibitor of heat shock protein 90 (Hsp90) and its derivatives had been designed by substituting various functional groups in the various position of five membered rings. A library of thirty nine derivatives was designed by introducing various functional groups such that amide, amine, phosphate, hydroxyl, fluorine, methoxy, and carboxylic acid in the active pharmacophore of oroidin. All the analyses expressed that seven analogues possessed better chemical activity and docking capabilities than that of the source molecule ODN. These seven computationally designed derivatives may be used as novel beneficial agents in various cancer therapies including breast, ovarian, colon, pancreas, liver carcinoma, and leukemia treatments, and could be considered to develop as effective anticancer drug candidates in the future. CHAPTER V Keeping in mind the importance of PDE4 inhibitors it includes a study where a quantitative structure-activity relationship (QSAR) modeling method was performed to develop a standard model on a dataset of sixty-six significant PDE4A inhibitors encompassing common scaffolds in pyrazolo-oxazine, and imidazo-pyridazine compounds. According to QSARINS software, the model comprises three descriptors namely MoRSEM11, MoRSEP26and MoRSEC11 were found to be the best ones. The three descriptor model which was employed to predict pIC50 values as the studied response exhibited good R2 (0.8185), and F (73.658) values. Internal validation parameters Q2loo= 0.7845, Q2LMO= 0.7771and external validation parameters Q2F1= 0.8277, Q2F2= 0.8246, Q2F3= 0.8626, confirmed the stability and robustness of the developed model. On the basis of this model equation, pIC50 values of thirty-nine designed compounds were calculated. The potent lead molecules, predicted from the QSAR model, were further investigated by performing in silico approaches such as molecular docking, molecular dynamics simulation, bioavailability assessments, and toxicity prediction. The study revealed that the eight compounds possessed potent PDE4A inhibitory activity and might be considered as future drugs subject to the viability of in situ and in vivo proceedings. CHAPTER VI In this chapter quantitative structure activity relationship (QSAR) model was built from a dataset of 44 compounds as LSD1 inhibitors. The best 10 compounds have fully satisfied all the criteria of drug-like properties and these designed lead molecules would have more potency to treat LSD1 target after going through in vivo and in vitro analysis. CHAPTER VII 3D-QSAR analysis and application of ANN validation in CADD to design potential inhibitors of many critical diseases in future.