About

Alzheimer’s disease is the leading cause of dementia with an estimated cost to the economy of $259 billion in the USA in 2017 alone. The disease is multifaceted and a clear molecular genesis or cause of the disease has to date not been unambiguously proven. To date several hypotheses to target drug development have been proposed including the cholinergic, amyloid-beta, tau, calcium channel and inflammation hypotheses. Divan’s research focused on the development of novel duel-inhibitors targeting the inhibition of acetyl choline clearance and aggregation of amyloid-beta through the inhibition of the catalytic triad and peripheral anionic site of acetyl cholinesterase. Research highlights include the development of structural analogues of the cholinesterase inhibitor Donepezil displaying  nano-molar activity against acetylcholinesterase with no cytotoxicity against neuroblastoma cell lines and the development of methodologies for the synthesis of tri- and tetracyclic scaffolds for the use as duel-target inhibitors.

Thesis

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

Dissertation

Targeting Alzheimer’s disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor Donepezil

Publications

3. Binding pose analysis of hydroxyethylamine based β-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors 

C. Johan van der Westhuizen, Divan G. van Greunen, Werner Cordier, Margo Nell, Vanessa Steenkamp, André Stander, Jenny-Lee Panayides and Darren L. Riley, Arkivoc2020, v, 84-107

β-Secretase (BACE1) is recognised as a target for the treatment of Alzheimer’s disease, and transition-state isosteres such as hydroxyethylamines have shown promise when incorporated into BACE1 inhibitors. A computational investigation of previously reported carbazole-based hydroxylethylamines with contradictory binding poses was undertaken using molecular dynamic simulations to rationalise the ligands preferred binding preference. Visual inspection of the confirmed binding pocket showed unoccupied space surrounding the carbazole moiety which was probed through the synthesis of seventeen ligands wherein the carbazole ring system was replaced with an indeno[1,2-b]indole ring system. The most active compound, rac-1-[benzyl(methyl)amino]-3-(indeno[1,2-b]indol-5(10H)-yl)propan-2-ol, indicated an inhibition of 91% at 10 μM against β-secretase with a cytotoxicity IC50 value of 10.51 ± 1.11 μM against the SH-SY5Y cell line.

* Regional issue – Organic Chemistry in South Africa*

2. Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease

D.G. van Greunen, C.J. van der Westhuizen, W. Cordier, M. Nell, A. Stander, C. van der Westhuyzen, V. Steenkamp, J.-L. Panayides, D.L. Riley. European Journal of Medicinal Chemistry 2019179, 680-693.

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ± 0.07 μM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ± 1.25 and 5.94 ± 1.08 μM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).

1. Targeting Alzheimer’s disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil.

D.G. van Greunen, W. Cordier, M. Nell, C. van der Westhuyzen, V. Steenkamp, J. Panayides, D.L. Riley. European Journal of Medicinal Chemistry 2017127, 671-690.

EJMedchem.jpg

A series of twenty seven acetylcholinesterase inhibitors, as potential agents for the treatment of Alzheimer’s disease, were designed and synthesised based upon previously unexplored chemical space surrounding the molecular skeleton of the drug donepezil, which is currently used for the management of mild to severe Alzheimer’s disease. Two series of analogues were prepared, the first looking at the replacement of the piperidine ring in donepezil with different sized saturated N-containing ring systems and the second looking at the introduction of different linkers between the indanone and piperidine rings in donepezil. The most active analogue 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (67) afforded an in vitro IC50value of 0.03 ± 0.07 μM against acetylcholinesterase with no cytotoxicity observed (IC50of >100 μM, SH-SY5Y cell line). In comparison donepezil had an IC50 of 0.05 ± 0.06 μM and an observed cytotoxicity IC50 of 15.54 ± 1.12 μM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.

Conferences

  1. SACI North Section – Young Chemist’s Symposium, Pretoria, South Africa, October 2017: Functionalization of previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil for the treatment of Alzheimer’s disease, D.G. van Greunen*, V. Steenkamp, J.-L. Panayides, D.L. Riley Presentation Prize
  2. 2016 Frank Warren Conference, Rhodes, South Africa, December 2016: Targeting Alzheimer’s Disease by Investigating Previously Unexplored Chemical Space Surrounding The Cholinesterase Inhibitor Donepezil, D.G. van Greunen*, W. Cordier, C. van der Westhuyzen, M. Nel, V. Steenkamp, J-L. Panayides, D.L. Riley
  3. 2016 Frank Warren Conference, Rhodes, South Africa, December 2016: Utilization of Flow Chemistry for the Synthesis of the Cholinesterase Inhibitor Donepezil, D.G. van Greunen*, J-L. Panayides, D.L. Riley Poster Prize
  4. 2016 Neuroscience Conference, South Africa, May, 2016: Targeting Alzheimer’s Disease By Investigating Previously Unexplored Chemical Space Surrounding The Cholinesterase Inhibitor Donepezil, D.G. van Greunen*, D.L. Riley, J-L. Panayides, V. Steenkamp, W. Cordier, C. van der Westhuyzen
  5. SAAWK, Bloemfontein, South Africa, October 2015: Ondersoek na voorheen onverkende chemiese ruimte rondom die asetielcholinesterase inhibeerder Donepezil, D.G. van Greunen*, D.L. Riley, J.-L.Panayides, V. Steenkamp, W. Cordier, C.W. van der Westhuyzen
  6. Pharmacology and Toxicology Congress, Johannesburg, South Africa, September 2015: Investigations into previously unexplored chemical space surrounding the acetylcholinesterase inhibitor Donepezil, D.G. van Greunen, D.L. Riley, J.-L.Panayides, V. Steenkamp, W. Cordier*, C.W. van der Westhuyzen
  7. 2015 Neuroscience Conference, Pretoria, South Africa, May 2015: Investigations into previously unexplored chemical space surrounding the acetylcholinesterase inhibitor Donepezil, D.G. van Greunen*, D.L. Riley, J.-L.Panayides, V. Steenkamp, W. Cordier, C.W. van der Westhuyzen
  8. Bi-National Organic Chemistry Conference, Stellenbosch, South Africa, December 2014: The synthesis of cholinesterase-inhibitors targeting Alzheimer’s disease, D.G. van Greunen*, D.L. Riley, J.-L. Panayides, V. Steenkamp

Posters