Further structure-activity relationship studies of schwarzinicine A analogues for vasorelaxant activity, and optimization of the total synthesis of schwarzinicine ATools Chan, Nathaniel Jia Yoong (2026) Further structure-activity relationship studies of schwarzinicine A analogues for vasorelaxant activity, and optimization of the total synthesis of schwarzinicine A. PhD thesis, University of Nottingham Malaysia.
AbstractDespite the availability of antihypertensive agents, resistant hypertension afflicts many individuals and requires multidrug regimens which contributes to issues regarding adherence and financial burden. Previously, a new phenethylamine alkaloid, schwarzinicine A, was isolated from a local fig tree, F. schwarzii, and was found to exhibit significant vasorelaxant effects in rat isolated aorta, making it a promising lead in the discovery of an antihypertensive that is effective against resistant hypertension. Therefore, a preliminary structure-activity relationship (SAR) study was performed through the synthesis of schwarzinicine A analogues, where several criteria for good activity and structural features that enhance vasorelaxation were identified. Analogues in the current study were designed to optimize the promising moieties revealed in the preliminary work to conduct a more in-depth SAR study and further improve potency. All synthesized analogues were evaluated for their vasorelaxant activity using the organ bath assay. Many SAR trends were observed through analysis of their activities. Of particular interest was analogue 113n, featuring a 3,4-dihydroxyphenyl ring C, which demonstrated the greatest potency of all analogues synthesized to date (112-fold better than schwarzinicine A). This is likely due to the formation of bifurcated hydrogen bonds between the pair of hydroxyl groups and the target site. Preliminary pharmacological studies were then conducted using analogue 113n to determine if it follows the schwarzinicine A mechanism of action or operates through additional pathways. The results suggest that 113n, like schwarzinicine A, induces vasorelaxation via Ca2+ channel modulation. Additionally, the four-step synthetic route to schwarzinicine A was also optimized and scaled up, with the overall percentage yield improved by 4.9-fold and the total reaction time shortened by 27 hours compared to the published method. This allows large quantities of schwarzinicine A to be produced in a cost- and time-efficient manner for future in vivo studies. These efforts have greatly enhanced knowledge surrounding schwarzinicine A and its analogues, which will ideally contribute to the production of an antihypertensive agent that can effectively manage resistant hypertension.
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