{"id":{"repo_id":"duquesne","oai_identifier":"oai:dsc.duq.edu:etd-1712"},"canonical_url":"https://search.dev.ndltd.org/etd/duquesne/oai:dsc.duq.edu:etd-1712","repository":{"repo_id":"duquesne","name":"Duquesne","base_url":"https://dsc.duq.edu/do/oai/"},"display":{"title":"Design and Synthesis of Novel Benzimidazoles and Aminothiazoles as Small Molecule Inhibitors of CDK5/p25","abstract":"This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation.","abstract_html":"This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation.","abstract_has_math":false,"creators":["Jain, Prashi"],"institution":null,"degree_name":"PhD","degree_level":"Immediate Access","degree_discipline":"Medicinal Chemistry","degree_department":null,"school":null,"contributors":["Patrick Flaherty","Aleem Gangjee","Marc Harrold","David Lapinsky","Jeffry Madura","James Drennen"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-01-01T08:00:00Z","date_published":"2011-01-01T08:00:00Z","updated_at":"2026-07-24T02:09:54Z","subjects":["Aminothiazole","Benzimidazoles","Buchwald reaction","CDK5","Drug design","Metal catalyzed reaction"],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://dsc.duq.edu/etd/696","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Patrick Flaherty","Aleem Gangjee","Marc Harrold","David Lapinsky","Jeffry Madura","James Drennen"]},{"key":"dc:creator","label":"Author","values":["Jain, Prashi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2018-03-28T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Medicinal Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Immediate Access"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Aminothiazole","Benzimidazoles","Buchwald reaction","CDK5","Drug design","Metal catalyzed reaction"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://dsc.duq.edu/etd/696"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation."]},{"key":"dc:title","label":"Title","values":["Design and Synthesis of Novel Benzimidazoles and Aminothiazoles as Small Molecule Inhibitors of CDK5/p25"]}]}],"canonical_facts":{"dc:contributor":["Patrick Flaherty","Aleem Gangjee","Marc Harrold","David Lapinsky","Jeffry Madura","James Drennen"],"dc:creator":["Jain, Prashi"],"dc:date.available":["2018-03-28T07:00:00Z"],"dc:description.abstract":["This dissertation describes the design, synthesis and biological evaluation of novel CDK5/p25 small molecule inhibitors. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase which plays an important role in the pathology of Alzheimer's disease (AD). CDK5/p25 has been implicated in hyperphosphorylation of tau protein which forms neurofibrillary tangles (NFTs), a contributing factor to the pathology of Alzheimer's disease (AD). Based on the deposited X-ray crystal structure of CDK5/p25 with a non-selective CDK inhibitor R-Roscovitine (PDB ID: 1UNL), eight series of novel compounds with a benzimidazole core were designed, synthesized and tested as inhibitors of CDK5/p25. An efficient synthesis of trisubtituted benzimidazoles was developed to explore the SAR at the 1-, 4-, and 6- positions of the benzimidazole core. X-ray crystal structure verification of an intermediate confirmed selective alkylation of the N-1 position of the benzimidazole scaffold. Synthesis of N-1, N-4, C6-O, C6-N, C6-C and C-2 substituted benzimidazoles were achieved via Mitsunobu coupling, Suzuki Miyaura coupling, Buchwald coupling and reductive alkylation strategies. Aminothiazole scaffolds are an established class of CDK inhibitors including CDK5. A molecular hybridization technique was applied to the design of a series of 2-, 5- disubstituted aminothiazoles incorporating structural features of both the Meriolins, natural product CDK inhibitors, and known aminothiazole scaffolds. Synthetic techniques employed included aryl lithiation, deoxygenation and acylation."],"dc:identifier":["https://dsc.duq.edu/etd/696"],"dc:language":["English"],"dc:subject":["Aminothiazole","Benzimidazoles","Buchwald reaction","CDK5","Drug design","Metal catalyzed reaction"],"dc:title":["Design and Synthesis of Novel Benzimidazoles and Aminothiazoles as Small Molecule Inhibitors of CDK5/p25"],"thesis:degree_discipline":["Medicinal Chemistry"],"thesis:degree_level":["Immediate Access"],"thesis:degree_name":["PhD"]},"updated_at":"2026-07-24T02:09:54Z"}