School of Pharmacy
Aminothiazole, Benzimidazoles, Buchwald reaction, CDK5, Drug design, Metal catalyzed reaction
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.
Jain, P. (2011). Design and Synthesis of Novel Benzimidazoles and Aminothiazoles as Small Molecule Inhibitors of CDK5/p25 (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/696