18. A reaction energy profile and fragment attributed molecular system energy change (FAMSEC)-based protocol designed to uncover reaction mechanisms: a case study of the proline-catalysed aldol reaction
I. Cukrowski, G. Dhimba and D.L. Riley, Physical Chemistry Chemical Physics 2019, 21, 16694-16705
A REP-FAMSEC (reaction energy profile-fragment attributed molecular system energy change) protocol designed to explain each consecutive energy change along the reaction pathway is reported. It mainly explores interactions between meaningful polyatomic fragments of a molecular system and, by quantifying energetic contributions, pin-points fragments (atoms) leading to or opposing a chemical change. Its usefulness is tested, as a case study, on the proline-catalysed aldol reaction for which a number of mechanisms have been debated for over four decades. The relative stability of S-proline conformers, their catalytic (in)activity and the superior affinity of the higher energy conformer to acetone is fully explained at atomic and molecular fragment levels, but still appealing to general chemist knowledge. We found that (i) contrary to the generally accepted view, CN-bond formation cannot be explained by the Nδ−, Cδ+ atom pair, but rather by the O-atom of acetone and its strongest inter-molecular attractive interactions with the N-atom as well as the C-atom of the COO group of proline (at this initial stage the lower energy conformer of proline is eliminated) and (ii) the following ‘first’ H-transfer from N to O atoms of the proline moiety is nearly energy-free even though initially the H-atom interacts three times stronger with the N- than O-atom; a full explanation of this phenomenon is provided.
17. 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 2019, 179, 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).
16. Landscape and opportunities for active pharmaceutical ingredient manufacturing in developing African economies
D.L. Riley, I. Strydom, R. Chikwamba and J.-L. Panayides, Reaction Chemistry and Engineering 2019, 4, 457-489
Africa is one of the world’s fastest growing economies, with South Africa having the fifth highest worldwide pharmaceutical expenditure per capita. In recent years, several companies have considered regional pharmaceutical production but have failed to make the investment, in stark contrast to the massive growth in pharmaceutical production in other BRICS countries. Major constraints identified have been the small local market, lack of skills, and an export-averse culture, which have prevented regional manufacturers from achieving the economies of scale that are essential to survive in a global market. In contrast, the pharmaceutical industry is undergoing a revolutionary change in manufacturing, with the potential to switch from batch manufacturing to continuous flow processing. The possibility of applying this new pharmaceutical business model in emerging markets will open the door for dramatic changes in regional commercial manufacturing. Advances in cloud computing, automation and system unification are paving the way for continuous active pharmaceutical ingredient production with integrated digital connectivity. This review will highlight the opportunities that exist in the localization of cutting-edge manufacturing technologies; in order to show the potential application of fundamental process research key production examples relevant to the region will be provided.
15. Immobilized tetrakis(triphenylphosphine)palladium(0) for Suzuki–Miyaura coupling reactions under flow conditions
G.V. Ramaotsoa, I. Strydom, J.-L. Panayides, D.L. Riley Reaction Chemistry and Engineering 2019, 4, 372-382
An immobilized triphenylphosphine scaffold was prepared by precipitation polymerization and functionalized to afford a cost-effective source of solid-supported tetrakis(triphenylphosphine)-palladium(0). The catalyst was characterised and used to perform biphasic Suzuki–Miyaura cross-coupling reactions using a packed-bed reactor under flow conditions. The approach afforded comparable yields to those obtained under batch conditions with a single pass through the packed-bed reactor (1 h vs. 18 h). The use of a recycling system was investigated on a model reaction and found to afford close to quantitative conversion within 3 hours.
14. Mild and selective reductions of aldehydes utilising sodium dithionite under flow conditions.
N.C. Neyt, D.L. Riley Beilstein Journal of Organic Chemistry 2018, 14, 1529-1536
We recently reported a novel hybrid batch–flow synthesis of the antipsychotic drug clozapine in which the reduction of a nitroaryl group is described under flow conditions using sodium dithionite. We now report the expansion of this method to include the reduction of aldehydes. The method developed affords yields which are comparable to those under batch conditions, has a reduced reaction time and improved space-time productivity. Furthermore, the approach allows the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process.
13. Approaches for performing reductions under continous flow conditions.
D. L. Riley, N.C. Neyt. Synthesis, 2018, 50 (14), 2707-2720
A concise overview of approaches to perform reductions of various functionalities including aldehydes, ketones, esters, imines, nitriles, nitro groups, alkenes and alkynes under continuous-flow conditions are highlighted and discussed in this short review.
12. Batch-flow hybrid synthesis of the anti-psychotic clozapine.
N.C. Neyt, D. L. Riley. Reaction Chemistry and Engineering, 2018, 3, 17-24.
The development of batch–flow hybrid processes is becoming an attractive prospect through which chemists can make use of the best aspects of both technologies. We have reported the implementation of an on-the-fly purification by trituration which can also be utilised to perform solvent swaps. We have demonstrated this concept through the synthesis of the antipsychotic clozapine. In addition, we report a novel means of performing a reduction of an aryl nitro group under flow conditions and an overall improved process route for the total synthesis of clozapine.
11. 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 2017, 127, 671-690.
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.
10. New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates
Riley, D. L.; Michael, J. P.; de Koning, C. B. Beilstein Journal of Organic Chemistry 2016, 12, 2609–2613.
A synthesis of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.
9. Design and synthesis of ring C opened analogues of α-santonin as potential anticancer agents
J. Khazir, B.A. Mir, L.A. Pilcher, D.L. Riley, G. Chashoo, A. Islam, A.K. Saxena, H.M.S. Kumar, Medicinal Chemistry Research, 2016, 25: 2030-2041.
Here we describe ring opening reaction of a novel halo triene derivative viz., (3S, 5aS)-8-chloro-3a, 4, 5, 5a-tetrahydro-3, 5a, 9-trimethylnaphtho [1, 2-b] furan-2(3H)-one of α-santonin upon nucleophillic attack with alcohols. Halo-triene was synthesized from α-santonin upon reaction with vilsmeier reagent. The synthesized compounds from ring opening reaction were evaluated for anticancer activity against a panel of four human cancer cell lines (A-549, THP-1, HCT-15, and IMR-13). Most of the compounds exhibited promising anticancer activity against all cancer cells in vitro; however compound. 3d with benzyl substitution showed most potent anticancer activity with an IC50 value of 0.3, 0.51, 0.6 and 0.23 μM against A-549, THP-1, HCT-116 and IMR-13 cell lines respectively.
8. An improved process for the preparation of tenofovir diisoproxil fumarate
D.L. Riley, D.R. Walwyn, C.D. Edlin, Organic Process Research and Development, 2016, 20, 742-750
The current three-step manufacturing route for the preparation of tenofovir disoproxil fumarate (1) was assessed and optimized leading to a higher yielding, simpler, and greener process. Key improvements in the process route include the refinement of the second stage through the replacement of the problematic magnesium tert-butoxide (MTB) with a 1:1 ratio of a Grignard reagent and tert-butanol. The development of a virtually solvent-free approach and the establishment of a workup and purification protocol which allows the isolation of a pure diethyl phosphonate ester (8) was achieved.
7. Design, synthesis and anticancer activity of Micheal-type thiol adducts of α-santonin analogue with exocyclic methylene
J. Khazir, D.L. Riley, G. Chashoo, B.A. Mir, D. Liles, A. Islam, S.K. Singh, R.A. Vishwakarma, L.A. Pilcher, European Journal of Medicinal Chemistry, 2015, 101, 769-779.
A series of Michael-type analogues were generated on the C-ring of α-santonin (α-methylene-γ-butyrolactone) upon reaction with various thiols. All the thiol adducts synthesized were evaluated for their anticancer activity against four human cancer cell lines (PC-3, HCT-15, A-549 and MCF-7). Bioassay results indicated that even though most of the synthesized compounds exhibited a good anticancer activity against various cancer cells in vitro, some of the compounds like 9e, 9g and 9q were found to be the most promising analogues in this series, with compound 9e showing IC50 values of 1.5 μM, 0.6 μM, 2.4 μM and 1.2 μM on PC-3, MCF-7, A-549 and HCT-116 cell lines respectively. Further, flow cytometry studies showed that MCF-7 cells treated with the compounds 9e, 9g and 9q were arrested in the sub G1 phase of the cell cycle in a concentration dependent manner. These lead molecules were further studied for NF-κB, p65 transcription factor inhibitory activity which confirmed concentration dependent inhibition against NF-κB, p65 with analogue 9e showing 57% inhibition at 2 μM, 9g showing 62% inhibition at 3 μM and 9q showing 54% inhibition at 2 μM concentration.
6. An inquiry-based practical curriculum for organic chemistry as preparation for industry and postgraduate research
L.A. Pilcher, D.L. Riley, K.C. Mathabathe, M. Potgieter, South African Journal of Chemistry, 2015 68, 236-244
This paper describes the development of a new practical curriculum for third-year organic chemistry to replace the recipe-based approach typically used in undergraduate teaching laboratories. The new curriculum consists of an inquiry-based project set in a simulated industrial context preceded by two scaffolding experiments to prepare students for the task. The industrial project requires students to evaluate experimentally three multi-step synthetic routes to a given target based on cost, technical challenge and environmental impact in order to make a recommendation as to which route the ‘company’ should use to synthesize the compound. The project equips students with technical skills suitable for both postgraduate research and industry, and develops metacognition and understanding through the use of the jig-saw cooperative learning strategy and reflection. The students were found to engage with the practical work at a deep intellectual level, demonstrating that contextualized inquiry-based laboratory teaching afforded an improved quality of learning. In addition, the reported practical curriculum made a difficult subject accessible and even popular, to some measure grew the students’ ability in all desired graduate attributes and resulted in the establishment of a professional identity for individual students.
5. Role of plants in anticancer drug discovery
J. Khazir, B.A. Mir, L. Pilcher, D.L. Riley, Phytochemistry Letters, 2014, 7, 173-181
Cancer is one of the major causes of death and the number of new cases, as well as the number of individuals living with cancer, is expanding continuously. Worldwide the alarming rise in mortality rate due to cancer has fuelled the pursuit for effective anticancer agents to combat this disease. Finding novel and efficient compounds of natural origin has been a major point of concern for research in the pharmaceutical sciences. Plants have been seen to possess the potential to be excellent lead structures and to serve as a basis of promising therapeutic agents for cancer treatment. Many successful anti-cancer drugs currently in use or their analogues are plant derived and many more are under clinical trials. This review aims to highlight the invaluable role that plants have played, and continue to play, in the discovery of anticancer agents.
*Phytochemistry Letters Top Cited Author 2014*
4. Anticancer agents from diverse natural sources
J. Khazir, D.L. Riley, L.A. Pilcher, P. De-Maayer, B.A. Mir, Natural Product Communications, 2014, 9, 1655-1669.
This review attempts to portray the discovery and development of anticancer agents/drugs from diverse natural sources. Natural molecules from these natural sources including plants, microbes and marine organisms have been the basis of treatment of human diseases since the ancient times. Compounds derived from nature have been important sources of new drugs and also serve as templates for synthetic modification. Many successful anti-cancer drugs currently in use are naturally derived or their analogues and many more are under clinical trials. This review aims to highlight the invaluable role that natural products have played, and continue to play, in the discovery of anticancer agents.
3. A process for the preparation of (R)-9-[2-(phosphonomethoxy)propyl]adenine (PMPA)
D.L. Riley, D.R. Walwyn, C.D. Edlin, WO2014033688 A1
This invention relates to a process for the preparation of (R)-9-[2- (phosphonometh-oxy)propyl]adenine (PMPA). This invention also relates to the preparation of Tenofovir disoproxil fumarate (TDF), a compound which can be produced from PMPA. The claimed process comprises reacting compound (6) with compound (7) in presence of 2,2,6,6- tetramethylpiperidinylmagnesium to compound (2), which is hydrolysed to (3).
2. Oxepines and Azepines
D.L. Riley and W.A.L. van Otterlo, in “Heterocycles in Natural Product Synthesis”, Editors: K.C. Majumdar and S.K. Chattopadhyay, Wiley-VCH Verlag, Weinheim Germany, 2011, 537-568.
Filling a gap on the market, this handbook and ready reference is unique in its discussion of the usefulness of various heterocyclic systems in the synthesis of natural products. Clearly structured for easy access to the information, each chapter is devoted to a certain class of heterocycle, providing a tabular presentation of the natural products to be covered containing the particular heterocyclic ring system along with their biological profile, occurrence and most important physical properties, backed by the appropriate references. In addition, the application of the heterocyclic system to the synthesis of natural products are covered in detail. Of great interest to organic, natural products, medicinal and biochemists, as well as those working in the pharmaceutical and agrochemical industry.
1. Formal synthesis of (5R,8R8aS)-indolizidine 209I via enaminones incorporating Weinreb amides
C.B. de Koning, J.P. Michael, D.L. Riley, Heterocycles, 2009, 79, 935-953
A formal enantioselective synthesis of the amphibian alkaloid (5R,8R,8aS)-(–)-indolizidine 209I (6) is reported. Control of the absolute stereochemistry at C-5 resulted from application of the Davies procedure, which entails stereoselective conjugate addition of (R)-(+)-N-benzyl-1-phenylethylamine to tert-butyl (E)-hex-2-enoate. The resulting chiral adduct 26 was converted in eight steps into a pivotal enaminone incorporating a Weinreb amide, the inherent nucleophilicity of which was exploited in a cyclisation that yielded the key bicyclic intermediate (5R)-N-methoxy- N-methyl-5-propyl-1,2,3,5,6,7-hexahydroindolizine- 8-carboxamide (38). Stereoselective catalytic hydrogenation of the alkene bond, reaction of the Weinreb amide with ethylmagnesium bromide, and epimerisation of the resulting ketone completed the formal synthesis of the target alkaloid.