Search

PhD (Pharmacy), North-West University, Potchefstroom Campus "Abstract not copied" Parkinson’s disease (PD) is now the fastest growing neurological condition worldwide, and regrettably, no drug stops, or at least, slows the neurodegeneration underlying this disease. Fortunately, coffee intake is associated with lower incidence of PD. Caffeine’s mechanism of action is non-selective adenosine receptor (AR) blockade, and as such; A₁ and/or A₂ᴀ AR antagonists hold promise for the potential treatment of PD. The flavonoids are a family of phytochemicals which are even more widespread in the human diet than the xanthine derivative caffeine. There is growing interest in this family of phytochemicals based on their health-related benefits. Notably, many flavonoids possess inhibition constant (Ki) values against ARs in the micromolar-range. As such, extended family members of the flavonoids, namely chalcones and the structurally related benzylidene indanones, -tetralones and benzoyl benzofurans may be a starting point for the design of non-xanthine based A₁ and A₂ᴀ AR antagonists. In order to identify novel AR ligands based on the chalcone scaffold; herein the synthesis, characterization and evaluation of almost 100 chalcones and structurally related compounds are reported. The degree and type of binding affinity that the test compounds showed toward rat (r) A₁ and/or A₂ᴀ ARs were determined via radioligand binding assays and GTP shift assays, respectively. The effect of selected test compounds on the viability of cultured Vero cells were assessed by means of an AlamarBlue®/resazurin assay. The pharmacokinetics, drug-likeness and medicinal chemistry friendliness of the selected test compounds were computed with SwissADME, a free web tool used to evaluate the key parameters of small molecules. Doctoral

MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus Parkinson's disease (PD), a classic movement disorder, is the second most common neurological condition after Alzheimer's disease, with higher incidence and prevalence in advanced age — consequently, PD patients' quality of life is reduced and, in addition, the disease has a high socio-economic cost. The pharmacological treatment of PD is based on the dopaminergic system and only addresses the motor symptoms of PD and not the non-motor symptoms (such as cognitive deficits and depression) or neurodegeneration. Additionally, L-3,4-dihydroxyphenylalanine (Levo-dopa/L-dopa) is associated with adverse effects such as motor and non-motor fluctuations, dyskinesias and drug-induced psychosis. Therefore, non-dopaminergic treatment that addresses motor and non-motor symptoms, as well as neurodegeneration, is in demand. The manipulation of adenosine receptors (AR's) may be the solution to the PD-conundrum, as an epidemiological study has established an association between the consumption of coffee or caffeine and a reduced risk of developing PD — caffeine is a xanthine derivative and non-selective A1 and A2A AR antagonist. The present study investigates novel, potent and selective A1 and A2A AR antagonists for the pharmacological treatment of PD. Most A1 and A2A AR antagonists are xanthine and non-xanthine derivatives. The xanthine core forms the basis of numerous potent and selective A1 and A2A AR antagonists, however, these compounds display low water solubility — limiting their in vivo application. This encouraged the design, synthesis and evaluation of non-xanthine derivatives, generally amino-substituted heterocyclic compounds. Additionally, the less explored N-free heterocyclic ring systems, such as flavonoids (exhibiting wide-ranging biological activity) — specifically aurones, may be a novel approach to non-xanthine A1 and A2A AR blockade. Structurally related to aurones are benzylidene tetralones, which also possess relatively good A1 and/or A2A AR antagonistic activity and selectivity. Therefore, the current study aimed to gain insight into the importance of structural modifications to ring A and B of the benzylidene tetralone scaffold necessary for A1 and/or A2A AR affinity in order to identify potential drug candidates for PD treatment. Acid catalysed aldol condensation reactions were used to synthesise novel benzylidene tetralones. The synthesised compounds were characterised via nuclear magnetic resonance (NMR) spectrometry, mass spectrometry (MS) and melting points. Furthermore, the purities of these compounds were determined by high performance liquid chromatography (HPLC). The A1 and/or A2A AR affinity of all synthesised compounds were ascertained by means of radioligand binding assays, while GTP shift assays determined selected compounds' functionality as A1 AR agonists or antagonists. It was found that C5-OH substitution on ring A of the benzylidene tetralones in combination with meta (C3')- and/or para (C4')-OH substitution on phenyl ring B of these scaffolds are ideal for A1 and/or A2A AR affinity. Furthermore, substitution of phenyl ring B of the benzylidene tetralones with a 2-aminopyrimidine ring resulting in moderate to high A2A AR affinity. In general, conversion from fused 6- and 5-membered rings (aurones) to fused 6- and 6-membered rings (2-benzylidene-1-tetralones) in combination with ring B substitutions improved A1 and A2A AR affinity. In conclusion, the current study involved the synthesis, characterisation and evaluation of novel 5-substituted 2-benzylidene-1-tetralone analogues to understand the importance of structural modifications to ring A and B of the aurone and 2-benzylidene-1-tetralone scaffold in gaining or even losing A1 and/or A2A AR affinity. The evaluated compounds are promising novel potent and selective A1 and/or A2A AR antagonists and, thus, possible lead compounds for the non-dopaminergic treatment of PD. Masters