Kokila Priya, S (2017) Design, Synthesis and Screening of Pyrazole Linked Thiazolidinones, Oxazepines and Benzoxazepines As Pf-Enr And E.Coli Fabi Inhibitors. Masters thesis, Sri Ramakrishna Institute of Paramedical Sciences, Coimbatore.
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Abstract
INTRODUCTION:Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design for the knowledge of the three-dimensional structure of the biomolecular target is equant but not necessarily relies on computer modelling techniques. This type of modelling is sometimes referred to as computer-aided drug design.PURPOSE AND PLAN OF WORK:The prime motivation of the present work is to design a drug in such a way that it can be used clinically to treat the disease. Drug discovery tools have been utilized now in designing new molecular entities which are safe and effective without consuming much of the research hours. Recent literatures shows that search of new drugs are now focussed on design of drugs as inhibitors of enzyme targets. Enoyl ACP reductase is such a potential drug target in the development of new antimicrobial agents. From the literature and virtual screening technique Triclosan analogues, pyrazole, thiazolidinone, oxazepine, etc., possess promising enoyl ACP reductase inhibiting action on both Plasmodium falciparum and Escherichia coli. Based on these reports an attempt was made here to design and develop new antiplasmodial and antibacterial agents by utilizing computational tools. The primary objective of the present work is to identify and synthesize pyrazole linked thiazolidinone, oxazepine and benzoxazepine as promising antiplasmodial and antibacterial agents by the inhibition of enoyl ACP reductase enzyme.SUMMARY:The present work was focused on the design, docking, synthesis and evaluation of antimalarial and antibacterial activity of Pyrazolyl linked thiazolidinone, oxazepine and benzoxazepine series as possible Enoyl ACP reductase inhibitors. Phase I - In-silico studies Selection of the target The enzyme involved in the fatty acid elongation of Plasmodium falciparum and Escherichia coli ie., Enoyl ACP reductase was selected as the drug target of the study. The corresponding enzyme were obtained from the protein data bank and their accession codes were 1VRW (PfENR) and 1C14 (E.coli Fab1). Selection of lead by virtual screening Virtual screening was performed by iGEMDOCK v.2. Forty nine hits were obtained from ZINC database, from which pyrazole, thiazolidinone and oxazepine were selected as the lead for inhibiting PfENR and E.coli FabI enzymes. Lead optimization The thirty modified ligands 2a-j, 3a-j and 4a-j were subjected to in-silico lead optimization. The ligands were optimized for evaluating oral bioavailability by utilizing the Molinspiration server. Lead optimization revealed that all the thirty selected derivatives possess good drug likeness score. Docking The optimized leads were subjected to docking studies using Autodock4.2 and the interactions of the derivatives with active sites of the enzymes were studied. The derivatives were subjected to interactions with PfENR and E.coli FabI. Triclosan was used as the standard ligand.CONCLUSION:The present study establishes that computational tools help in minimizing the tedious process of drug discovery and delivers new drug candidate more quickly. Virtual screening was utilized for filtering the compounds and selecting the lead compounds. The drug likeness score established the compounds to be pharmacokinetically active. The binding energy obtained from docking study further confirmed the possibility of the affinity of the selected leads towards the enzyme, enoyl ACP reductase from Plasmodium falciparum and Escherichia coli. Using the schemes various pyrazolyl linked thiazolidinone, oxazepine and benzoxazepine were synthesized with good yield. Structure of the synthesized compounds were confirmed by Melting point, TLC, UV, NMR and MASS spectra. The compounds were screened for antimalarial and antibacterial activity. Thus the present study depicts that the utilization of computer aided drug design is an efficient tool in predicting the effectiveness of a series of compounds under study and thus can result in the design of potent antimalarial and antibacterial agents.
| Item Type: | Thesis (Masters) |
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| Additional Information: | REG.No.261515102 |
| Uncontrolled Keywords: | Design ; Synthesis; Pyrazole Linked Thiazolidinones; Oxazepines ; Benzoxazepines ; Pf-Enr ; E.Coli Fabi Inhibitors |
| Subjects: | PHARMACY > Pharmaceutical Chemistry |
| Depositing User: | Ravindran C |
| Date Deposited: | 16 Mar 2018 06:13 |
| Last Modified: | 16 Mar 2018 06:27 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/6315 |
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