The design, synthesis and biological evaluation of novel compounds against biomarkers of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease accounting for an estimated 60 – 80 % of dementia cases. The disease affected 5.5 million Americans older than 65 years in 2018 alone, and this number is projected to increase to 13.8 million by 2050. The total cost of care in the United States for people with AD was $277 billion in 2018, making it one of the costliest diseases to treat. Statistics on the prevalence of dementia in South Africa are very limited and according to a study performed in the rural areas of the Eastern Cape in 2017, it was estimated that 352 000 individuals older than 60 are living with dementia. Unfortunately, there are currently no approved therapies which target AD pathology directly and therefore current treatments focus on relieving symptomatic and behavioral aspects of AD. Thus, a lot of focus has been placed on the development of new drugs for different biomarkers as potential treatment of AD. This study consists of the design, synthesis and biological evaluation of novel compounds against biomarkers of AD. In this study, four different series of compounds, consisting of ninety-one analogues, were synthesized as novel compounds against biomarkers of AD. These included; (i) series 1: N-benzylpiperidine carboxamide derivatives; (ii) series 2: 1-(5,6-dimethoxy-8H-indeno[1,2-d]thiazole-2-yl)urea derivatives; (iii) series 3: 1-amino-3-(indeno[1,2-b]indol-5(10H)-yl)propan-2-ol derivatives; and (iv) series 4: 6,7-dimethoxy-1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide derivatives. All compounds were evaluated for activity against acetylcholinesterase (AChE), the major biomarker of AD. Derivatized compounds of series 1 were assessed for activity against butyrylcholinesterase (BuChE). Derivatized compounds of series 3 were assessed for activity against the amyloid precursor protein cleaving enzyme 1 (BACE1). The first series of fifteen compounds based upon the skeleton of 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate, a compound previously synthesized, were synthesized and evaluated for activity against acetylcholinesterase. A second series of thirty-five compounds designed to have dual acetylcholinesterase and glycogen synthase kinase 3 inhibitory activity, were synthesized based upon the skeleton of 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide. A third series of seventeen compounds with potential β-secretase 1 inhibitors were designed and synthesized based upon the skeleton of 1-(3,6-dichloro-9H-carbazol-9-yl)-3-(naphthalen-1-ylamino)propan-2-ol, a compound previously reported in literature by Macchia and co-workers. A fourth series consisting of twenty-four potential N-methyl-D-aspartate (NMDA) receptor antagonists were designed and synthesized based upon scaffolds previously reported in the literature by the Liotta and Kawai research groups. In order to prepare large quantities of donepezil for use as a stock reagent for the development of libraries of potential BACE1 inhibitors, the preparation of donepezil using continuous flow conditions was attempted. The highest yield obtained for the benzylation of ethyl isonipecotate was 83% at 90 °C with a residence time of 45 minutes as compared to the batch process which took 3 hours to complete with a yield of 79%. Reduction of the (E)-2-[(1-benzylpiperidin-4-yl)methylene]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one to afford the final product donepezil was obtained with a yield of 80% after 4.5 hours, with no observable de-benzylation in flow as compared to the batch process which was completed after 6 hours with a yield of 78%. Due to time constraints, Stage 2 of the flow synthesis of donepezil could not be completed. However, with only two of the three steps completed for the flow process, the yield of the individual steps was already improved, and there was a reduction in the reaction time.