Design and Synthesis of Novel Benzimidazoles and Aminothiazoles as Small Molecule Inhibitors of CDK5/p25

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.

Name thesis:degree_name

PhD

Level thesis:degree_level

Immediate Access

Discipline thesis:degree_discipline

Medicinal Chemistry

Year dc:date.available

2011

Author dc:creator

• Jain, Prashi

Contributors dc:contributor

• Patrick Flaherty
• Aleem Gangjee
• Marc Harrold
• David Lapinsky
• Jeffry Madura
• James Drennen

• Aminothiazole
• Benzimidazoles
• Buchwald reaction
• CDK5
• Drug design
• Metal catalyzed reaction

Language dc:language

English

Repository record dc:identifier

https://dsc.duq.edu/etd/696

OAI identifier oai:identifier

oai:dsc.duq.edu:etd-1712