Synthesis, antiplasmodial activity and in silico molecular docking study of pinocembrin and its analogs
Authors: Melaku Yadessa , Solomon Melat , Eswaramoorthy Rajalakshmanan , Beifuss Uwe , Ondrus Vladimir , Mekonnen Yalemtsehay 
Published: May 2022

Background

Malaria remains the major health problem responsible for many mortality and morbidity in developing countries. Because of the development of resistance byPlasmodiumspecies, searching effective antimalarial agents becomes increasingly important. Pinocembrin is a flavanone previously isolated as the most active antiplasmodial compound from the leaves ofDodonaea angustifolia. For a better understanding of the antiplasmodial activity, the synthesis of pinocembrin and a great number of analogs was undertaken.

Methods

Chalcones5a-rwere synthesized via Claisen-Schmidt condensation using 2,4-dibenzyloxy-6-hydroxyacetophenone and aromatic aldehydes as substrates under basic conditions. Cyclization of compounds5a-rto the corresponding dibenzylated pinocembrin analogs6a-rwas achieved using NaOAc in EtOH under reflux. Catalytic hydrogenation using 10% Pd/C as catalyst in an H-Cube Pro was used for debenzylation to deliver7a-l. The structures of the synthesized compounds were characterized using various physical and spectroscopic methods, including mp, UV, IR, NMR, MS and HRMS. The synthesized dibenzylated flavanones6a-d, 6iand7awere evaluated for their in vivo antiplasmodial activities againstPlasmodium bergheiinfected mice. Molecular docking simulation and drug likeness properties of compounds7a-lwere assessed using AutoDock Vina and SwissADME, respectively.

Results

A series of chalcones5a-rhas been synthesized in yields ranging from 46 to 98%. Treatment of the chalcones5a-rwith NaOAc refluxing in EtOH afforded the dibenzylated pinocembrin analogs6a-rwith yields up to 54%. Deprotection of the dibenzylated pinocembrin analogs delivered the products7a-lin yields ranging from 78 to 94%. The dibenzylated analogs of pinocembrin displayed percent inhibition of parastaemia in the range between 17.4 and 87.2% at 30 mg/kg body weight. The parastaemia inhibition of 87.2 and 55.6% was obtained on treatment of the infected mice with pinocembrin (7a) and 4’-chloro-5,7-dibenzylpinocembrin (6e), respectively. The mean survival times of those infected mice treated with these two compounds were beyond 14 days indicating that the samples suppressedP. bergheiand reduced the overall pathogenic effect of the parasite. The molecular docking analysis of the chloro derivatives of pinocembrin revealed that compounds7a-lshow docking affinities ranging from – 8.1 to – 8.4 kcal/mol while it was -7.2 kcal/mol for chloroquine.

Conclusion

Pinocembrin (7a) and 4’-chloro-5,7-dibenzyloxyflavanone (6e) displayed good antiplasmodial activity. The in silico docking simulation againstP. falciparumdihydrofolate reductase-thymidylate synthase revealed that pinocembrin (7a) and its chloro analogs7a-lshowed better binding affinity compared with chloroquine that was used as a standard drug. This is in agreement with the drug-like properties of compounds7a-lwhich fulfill Lipinski's rule of five with zero violations. Therefore, pinocembrin and its chloro analogs could serve as lead compounds for further antiplasmodial drug development.