Synthesis and Antiprion SAR Studies of α,β-Unsaturated Carbonyl Compounds and Their Derivatives using a Flow Reactor

Chalcone is an alternative name for an α,β-unsaturated carbonyl compound. The system consists of two aromatic rings linked together by a three aliphatic carbon bridge. In the last few years, chalcones and their derivatives have become one of the interesting compounds that show significant activity in reducing PrPSc levels and for this reason these types of compounds were chosen as lead compounds for this project. Different series’ of chalcones were synthesised via aldol condensation under continuous flow conditions. The first route consists of the reaction between 4-(benzyloxy)-3-methoxybenzaldehyde and different substituted acetophenones. The second route contains the indole moiety, these compounds were synthesised from the reaction between 1H-indol-6-carbaldehyde and different substituted acetophenones. A new chalcone was synthesised from 3-((1H-pyrazol-1-yl)methyl)-4-methoxybenzaldehyde which was treated with acetophenone forming the corresponding chalcone. The synthesised chalcone was then used to synthesise two types of pyrrolones containing the moiety of 5-hydroxy-pyrrolidin-2-one (γ-hydroxy-γ-lactam). Three different types of amines were used to synthesise the fourth type of chalcones. The amines were reacted with 4-flourobenzaldehyde forming the corresponding aldehydes which were treated with a variety of heterocylic ketones to produce the corresponding chalcones. Three types of bischalcones were also synthesised from the reaction between 4-(1H-pyrazol-1-yl)benzaldehyde and different ketones. Chalcones containing the quinoline moiety were synthesised in four steps starting from m-toluidine to form the aldehyde which was treated with a variety of acetophenones forming the corresponding chalcones.
The ketothylinic group of the chalcones were cyclized into the corresponding pyrazolines by treating them with hydrazine monohydrate using ionic solvent under continuous flow conditions.
Finally, all the synthesised chalcones and their derivatives were screened for their antiprion activity and to investigate the antiprion structure-activity relationship. Amongst 51 chalcones and their derivatives 27 compounds were found to be active as antiprion agents. The Best EC50 values were found in compounds 154 (EC50 = 0.097µM), 155 (EC50 = 0.0103 µM), 163b (EC50 = 0.1 µM), 171 (EC50 = 0.1 µM), 179 (EC50 = 0.14 µM), 180 (EC50 = 0.10 µM), 181 (EC50 = 0.54 µM), 182 (EC50 = 0.01 µM) and 183 (EC50 = 0.03 µM).