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dc.contributor.advisorCanney, Daniel J.
dc.contributor.advisorAbou-Gharbia, Magid
dc.creatorAnnadurai, Sivakumar
dc.date.accessioned2020-10-20T13:33:22Z
dc.date.available2020-10-20T13:33:22Z
dc.date.issued2011
dc.identifier.other864885762
dc.identifier.urihttp://hdl.handle.net/20.500.12613/695
dc.description.abstractIn drug discovery there are several approaches to lead generation and one traditional approach involves the synthesis and screening of a structurally diverse compound library against a number of biological targets to identify high affinity lead compounds. The use of a `privileged' structure-based compound library represents a viable approach that could lead to drug like lead compounds. Privileged structures are defined as those ligand substructures that may be used to generate high affinity leads for more than one type of receptor. Examples of privileged structures include phenyl substituted monocycles such as biphenyls, diphenyl methane derivatives, 1,4-dihydropyridines, fused ring systems such as chromones, quinoxalines, quinazolines, 2-benzoxazolones, indoles, benzimidazoles and benzofurans. There are several instances in the literature describing the development of compound libraries based on privileged structures with reportedly high hit rates. Privileged structure based approaches has been used with notable success in the identification of high affinity ligands especially for G-protein coupled receptors (GPCRs). The scaffold 2-aminothiazole (fused and non-fused) may be considered a privileged structure because of its occurrence in a wide variety of pharmaceuticals. The scaffold is found in antibacterials, anti-inflammatory agents, glutamate transporter (GLT-1) modulators, serotonin and muscarinic ligands. The present study involves the synthesis of a 2-aminothiazole (fused and non-fused) based compound library (60 compounds) by incorporating bioactive fragments shown to produce hits in the biological targets of interest. Microwave assisted organic synthesis (MAOS) has been employed at key steps of scaffold synthesis as well as in Suzuki coupling to generate the target aminothiazoles. Preliminary biological screening has resulted in the identification of some promising lead compounds. Trifluoromethoxy substituted aminothiazoles were found to be potent antimicrobials with MIC values in the range of 4-16 microgram/ml. Furanone based aminothiazoles showed affinity for muscarinic receptors. Piperidine based aminothiazoles showed greater than 90% of control (8-OH-DPAT) specific agonist response at the 5-HT1A receptor subtype. The Clog P values of the most potent antimicrobials were found to be in the range of 4.5-6.2 indicating the high lipophilicity of the compounds. High lipophilicity is known to cause solubility issues that may hamper future development. Therefore in an effort to make compounds with intermediate lipophilicity, the phenyl core of the potent aminothiazoles will be replaced with pyridine core using literature procedures (Pyridine core containing aminothiazoles showed Clog P < 4). Future plans include expanding the library, improving the yields of compounds and to evaluate the compounds as modulators of glutamate transporter (GLT-1). The work could be extended to include other privileged structures such as 2-aminooxazole, 2-aminobenzoxazole, 2-aminoimidazole and 2-aminobenzimidazole. These mono and bicyclic heterocyles may be considered bioisosteres of 2-aminothiazole.
dc.format.extent362 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectPharmaceutical Sciences
dc.subject2-aminothiazole
dc.subjectAntimicrobial
dc.subjectLead Generation Approaches
dc.subjectMuscarinic Ligands
dc.subjectPrivileged Structure
dc.subjectSerotonin Ligands
dc.titleLead generation using a privileged structure-based approach
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberBorenstein, Michael R.
dc.contributor.committeememberIlies, Marc A.
dc.contributor.committeememberHarrison, Boyd L.
dc.description.departmentPharmaceutical Sciences
dc.relation.doihttp://dx.doi.org/10.34944/dspace/677
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-10-20T13:33:22Z


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