ResearchSpace :: Browsing by Author "Panayides, Jenny-Lee"

Browsing by Author "Panayides, Jenny-Lee"

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Anti-mycobacterial peroxides: A new class of agents for development against tuberculosis
(2020) Van der Westhuyzen, Christiaan W; Haynes, J; Panayides, Jenny-Lee; Wiid, I; Parkinson, C
Background: With few exceptions, existing tuberculosis drugs were developed many years ago and resistance profiles have emerged. This has created a need for new drugs with discrete modes of action. There is evidence that tuberculosis (like other bacteria) is susceptible to oxidative pressure and this has yet to be properly utilised as a therapeutic approach in a manner similar to that which has proven highly successful in malaria therapy. Objective: To develop an alternative approach to the incorporation of bacterial siderophores that results in the creation of antitubercular peroxidic leads for subsequent development as novel agents against tuberculosis. Methods: Eight novel peroxides were prepared and the antitubercular activity (H37Rv) was compared to existing artemisinin derivatives in vitro. The potential for toxicity was evaluated against the L6 rat skeletal myoblast and HeLa cervical cancer lines in vitro. Results: The addition of a pyrimidinyl residue to an artemisinin or, preferably, a tetraoxane peroxidic structure results in antitubercular activity in vitro. The same effect is not observed in the absence of the pyrimidine or with other heteroaromatic substituents. Conclusion: The incorporation of a pyrimidinyl residue adjacent to the peroxidic function in an organic peroxide results in anti-tubercular activity in an otherwise inactive peroxidic compound. This will be a useful approach for creating oxidative drugs to target tuberculosis.
Assessing a sustainable manufacturing route to lapatinib
(2022-08) Stark, RT; Rye, DR; Newton, OJ; Deadman, BJ; Miller, PW; Panayides, Jenny-Lee; Riley, Darren L; Helldardt, K; Hii, KK
A synthetic route to an anti-cancer drug, lapatinib, was devised to support the development of a sustainable manufacturing process in South Africa. Quantitative metrics were employed to evaluate the sustainability of the key steps of the reaction.
Binding pose analysis of hydroxyethylamine based ß-secretase inhibitors and application thereof to the design and synthesis of novel indeno[1,2-b]indole based inhibitors
(2020-11) Van der Westhuizen, CJ; Van Greunen, DG; Cordier, W; Nell, M; Steenkamp, V; Stander, A; Panayides, Jenny-Lee; Riley, DL
ß-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 ß-secretase with a cytotoxicity IC50 value of 10.51 ± 1.11 µM against the SH-SY5Y cell line.
Design and testing of an ozonolysis reactor module with on-the-fly ozone degassing under flow conditions
(2022-03) Neyt, Nicole C; Van der Westhuizen, Johan C; Panayides, Jenny-Lee; Riley, DL
Ozonolysis is an attractive, efficient, and green means of introducing oxygen containing functionalities using only oxygen and electricity. Unfortunately, safety issues associated with the accumulation of dissolved ozone and potentially explosive ozonides coupled with an oxygen rich reaction atmosphere have limited its integration into large scale process reactions. Herein we report on the development and testing of a prototype flow-based ozonolysis reactor which allows on-the-fly removal of ozone and oxygen negating the need for a downstream degassing step and allowing the continuous processing of intermediate ozonides in a safe manner. The approach lends itself to being able to telescope directly into downstream reactions without concern for the effect of residual ozone and minimises contact between the oxygen rich ozone atmosphere and the reaction mixture. The prototype was shown to remove between 98.5 and 99.7% of residual ozone-oxygen on-the-fly and its performance was demonstrated through the ozonolysis of several alkenes to afford a range of oxygen containing functional groups in good to high yields.
Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives
(Wiley Online Library, 2016-01) Ngwane, AH; Panayides, Jenny-Lee; Chouteau, F; Macingwana, L; Viljoen, A; Baker, B; Madikane, E; De Kock, C; Wiesner, L; Chibale, K; Parkinson, CJ; Mmutlane, EM; Van Helden, P; Wiid, I
A series of 2(5H)-furanone-based compounds were synthesized from commercially available mucohalic acids. From the first-generation compounds, three showed inhibitory activity (10 µg/mL) of at least 35% against Mycobacterium smegmatis mc(2) 155 growth (Bioscreen C system). In screening the active first-generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC99 ) of 8.07 µg/mL (15.8 µM) using BACTEC 460 system. No cross-resistance was observed with some current first-line anti-TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram-positive and Gram-negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time-kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Hamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti-TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 µg/mL (5.6 µM) and 3.07 µg/mL (5.6 µM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC50 = 38.24 µg/mL to IC50 =45.58 µg/mL when compared to the most active first-generation compound (IC50 =1.82 µg/mL).The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti-TB drug candidates.
Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations
(2022-03) Van van der Westhuizen, Johan C; Stander, A; Riley, DL; Panayides, Jenny-Lee
Alzheimer's disease is the most common neurodegenerative disease and currently poses a significant socioeconomic problem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors of acetylcholinesterase, a target for Alzheimer's disease. High-throughput virtual screening was employed to predict potential inhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble of binding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submitted for in vitro screening, which led to 25 hits being identified with IC50 values of less than 50 µM. The majority of these hits belonged to two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo[3,2-c]pyridin-6-amine both of which are noted to be promising compounds for further optimization. As various possible binding poses were suggested from molecular docking, molecular dynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stable water bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets of compounds that are not able to form this water bridge.
Evaluating blood–brain barrier permeability, cytotoxicity, and activity of potential acetylcholinesterase inhibitors: In vitro and in silico study
(2024-12) Maboko, LM; Theron, Anjo; Panayides, Jenny-Lee; Cordier, W; Fisher, D; Steenkamp, V
Acetylcholinesterase inhibitors (AChEIs) remain the first-line treatment for Alzheimer's disease. However, these drugs are largely symptomatic and often associated with adverse effects. This study aimed to evaluate novel pharmacophores for their in vitro AChEI activity, blood–brain barrier (BBB) permeability, and cytotoxic potential, hypothesizing that a combination of AChEIs could enhance symptom management while minimizing toxicity. A library of 1453 synthetic pharmacophores was assessed using in vitro and in silico methods to determine their feasibility as an inhibitor of the AChE enzyme. An in-house miniaturized Ellman's assay determined acellular AChEI activities, while pharmacokinetic properties were evaluated using the SwissADME web tool. The combinational effects of in silico BBB-permeable pharmacophores and donepezil were examined using a checkerboard AChEI assay. Cytotoxicity of active compounds and their synergistic combinations was assessed in SH-SY5Y neuroblastoma and bEnd.5 cells using the sulforhodamine B assay. Cellular AChEI activity of active in silico BBB-permeable predicted compounds was determined using an SH-SY5Y AChE-based assay. An in vitro BBB model was used to assess the effect of compounds on the integrity of the bEnd.5 monolayer. Out of the screened compounds, 12 demonstrated 60% AChEI activity at 5 μM, with compound A51 showing the lowest IC50 (0.20 μM). Five compounds were identified as BBB-permeable, with the donepezil-C53 combination at ¼IC50 exhibiting the strongest synergy (CI = 0.82). Compounds A136 and C129, either alone or with donepezil, showed cytotoxicity. Notably, compound C53, both alone and in combination with donepezil, demonstrated high AChEI activity and promising BBB permeability, warranting further investigation.
Landscape and opportunities for active pharmaceutical ingredient manufacturing in developing African economies
(Royal Society of Chemistry, 2019) Riley, DL; Strydom, I; Chikwamba, Rachel K; Panayides, Jenny-Lee
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.
Rapid formation of 2-lithio-1-(triphenylmethyl)imidazole and substitution reactions in flow†
(2021-09) Wang, S; Panayides, Jenny-Lee; Riley, D; Tighe, CJ; Hii, KK
The functionalisation of imidazoles is a necessary step in the formation of many active pharmaceutical intermediates. Herein, we report a flow chemistry approach for the rapid and efficient formation of 2-lithio-1-(triphenylmethyl)imidazole at ambient temperature and its reaction with a range of electrophiles, achieving modest to high yields (40–94%) in short reaction times (<1 min). The method is amenable to the scale-up of this highly reactive lithio-imidazole intermediate.
Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides
(Elsevier, 2016-06) Panayides, Jenny-Lee; Mathieu, V; Banuls, LMY; Apostolellis, H; Dahan-Farkas, N; Davids, H; Harmse, L; Rey, MEC; Green, IR; Pelly, SC; Kiss, R; Kornienko, A; Van Otterlo, WAL
Seventeen silyl- and trityl-modified (5'-O- and 3',5'-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100 µM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI(sub50) values, with the best results being values of 25 µM.
The synthesis of bupropion hydrochloride under greener and safer conditions utilizing flow technologies
(2024-01) Van Wyk, LT; Neyt, Nicole C; Jugmohan, Jaimee; Panayides, Jenny-Lee; Riley, DL
Globally, major depressive disorders are a leading cause of disconsolateness affecting more than 300 million individuals. Bupropion is a unique dopamine-norepinephrine reuptake inhibitor (DNRI) commonly utilized in the treatment of depression, smoking cessation, ADHD and other addictions. Herein, we report our attempts to develop a greener, safer and more sustainable process for the preparation of bupropion hydrochloride employing flow chemistry. The use of obnoxious and corrosive liquid bromine was evaded through the employment of polymer-bound pyridinium tribromide and environmentally questionable solvents NMP and DMF were substituted with greener co-solvent systems with appreciable success. The final telescoped flow process afforded bupropion hydrochloride in a 69% overall yield, with improved process mass intensity, productivity and purity, as well as a reduction in reagents/solvents designated as red or amber in terms of H-codes.
Targeting Alzheimer's disease by investigating previously unexplored chemical space surrounding the cholinesterase inhibitor donepezil
(Elsevier, 2017-02) Van Greunen, DG; Cordier, W; Nell, M; Van der Westhuyzen, Christiaan W; Steenkamp, V; Panayides, Jenny-Lee; Riley, DL
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 IC(sub50) value of 0.03 ± 0.07 µM against acetylcholinesterase with no cytotoxicity observed (IC(sub50) of >100 µM, SH-SY5Y cell line). In comparison donepezil had an IC(sub50) of 0.05 ± 0.06 µM and an observed cytotoxicity IC(sub50) of 15.54 ± 1.12 µM. Molecular modelling showed a strong correlation between activity and in silico binding in the active site of acetylcholinesterase.
The role of silicon in drug discovery: A review
(2024-10) Panayides, Jenny-Lee; Riley, DL; Hasenmaile, F; Van Otterlo, WAL
This review aims to highlight the role of silicon in drug discovery. Silicon and carbon are often regarded as being similar with silicon located directly beneath carbon in the same group in the periodic table. That being noted, in many instances a clear dichotomy also exists between silicon and carbon, and these differences often lead to vastly different physiochemical and biological properties. As a result, the utility of silicon in drug discovery has attracted significant attention and has grown rapidly over the past decade. This review showcases some recent advances in synthetic organosilicon chemistry and examples of the ways in which silicon has been employed in the drug-discovery field.
Use of open-source software platform to develop dashboards for control and automation of flow chemistry equipment
(2022-07) Van der Westhuizen, Johan; Du Toit, Jurie H; Neyt, Nicole C; Riley, DL; Panayides, Jenny-Lee
We report the development of an open-source software approach to monitor and control flow chemistry reactors from any smart device utilising Node-RED which lowers the expertise required to expand the system further and automate other equipment. The software was demonstrated through the control and automation of flow equipment from Uniqsis with the dashboard server run on a low-cost Raspberry Pi. Parameters of the equipment can be saved to a database for review in real-time or at a later stage. The dashboard control platform was demonstrated by performing the allylation of isovanillin in a semi-autonomous closed-loop optimisation fashion using Summit for the optimisation algorithm. The space time yield (STY) was optimised for this reaction using a single-objective Bayesian optimisation (SOBO) approach. The best STY result of 791 g dm-3 h-1 was achieved with the experimental conditions of 77.3 °C for the reactor column, a residence time of 4 min, with 1.005 equivalence of allyl bromide. All the software utilised in this paper was open-source, a tutorial-based approach to developing the program is included in the paper demonstrating the software capabilities.

Browsing by Author "Panayides, Jenny-Lee"

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