Synthesis, antiplasmodial activity and in silico molecular docking study of pinocembrin and its analogs

Abstract

Background Malaria remains the major health problem responsible for many mortality and morbidity in developing countries. Because of the development of resistance by Plasmodium species, searching effective antimalarial agents becomes increasingly important. Pinocembrin is a flavanone previously isolated as the most active antiplasmodial compound from the leaves of Dodonaea angustifolia. For a better understanding of the antiplasmodial activity, the synthesis of pinocembrin and a great number of analogs was undertaken. Methods Chalcones 5a-r were synthesized via Claisen-Schmidt condensation using 2,4-dibenzyloxy-6-hydroxyacetophenone and aromatic aldehydes as substrates under basic conditions. Cyclization of compounds 5a-r to the corresponding dibenzylated pinocembrin analogs 6a-r was 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 deliver 7a-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 flavanones 6a-d, 6i and 7a were evaluated for their in vivo antiplasmodial activities against Plasmodium berghei infected mice. Molecular docking simulation and drug likeness properties of compounds 7a-l were assessed using AutoDock Vina and SwissADME, respectively. Results A series of chalcones 5a-r has been synthesized in yields ranging from 46 to 98%. Treatment of the chalcones 5a-r with NaOAc refluxing in EtOH afforded the dibenzylated pinocembrin analogs 6a-r with yields up to 54%. Deprotection of the dibenzylated pinocembrin analogs delivered the products 7a-l in 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 suppressed P. berghei and reduced the overall pathogenic effect of the parasite. The molecular docking analysis of the chloro derivatives of pinocembrin revealed that compounds 7a-l show 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 against P. falciparum dihydrofolate reductase-thymidylate synthase revealed that pinocembrin (7a) and its chloro analogs 7a-l showed better binding affinity compared with chloroquine that was used as a standard drug. This is in agreement with the drug-like properties of compounds 7a-l which 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.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Melaku and co-workers revealed pinocembrin (13, active constituent obtained from the leaves of D. Angustifolia) and its analogue (14, Figure 7) as anti-plasmodial agents with parasitaemia inhibition of 87.2 and 55.6 %, respectively in infected mice. [49] Further, both the compounds, complying with Lipinski's rule of five, were found with good binding affinity with PfDHFRthymidylate synthase disclosed in comparison with chloroquine. [50] Cho et al performed the SAR investigation on 2,3,4,9tetrahydro-1H-β-carbolines clubbed with 2-((coumarin-5-yl)oxy) alkanoyl moiety starting from identified hit (15, IC 50 of 20 nM) by cell-based phenotypic screening.…”

“…Melaku and co‐workers revealed pinocembrin ( 13 , active constituent obtained from the leaves of D. Angustifolia ) and its analogue ( 14 , Figure 7) as anti‐plasmodial agents with parasitaemia inhibition of 87.2 and 55.6 %, respectively in infected mice [49] . Further, both the compounds, complying with Lipinski's rule of five, were found with good binding affinity with Pf DHFR‐thymidylate synthase disclosed in comparison with chloroquine [50]…”

Microencapsulation, Physicochemical Characterization, and Antioxidant, Antibacterial, and Antiplasmodial Activities of Holothuria atra Microcapsule

“…Nine terpenoid compounds were selected for modeling and antiplasmodial testing using an in silico approach. Assessing antiplasmodial activity in silico entails utilizing computational techniques to forecast a compound's ability to hinder the growth of Plasmodium parasites responsible for malaria [ 25 ]. The structures of nine terpenoids, namely, 17-hydroxyfuscocineroside B (CID 25099007), holothurin A3 (CID 71728339), holothurin A1 (CID 102057279), calcigeroside B (CID 163105984), fuscocineroside C (CID 44559164), holothurin B (CID 23674754), Echinoside A (CID 156831), 24-dehydroechinoside B (CID 101610324), and echinoside B (CID 73999936), were retrieved from the PubChem NCBI database.…”

Screening Carica Papaya Compounds as an Antimalarial Agent: In Silico Study

“…Dihydropyrimidine acts as an inhibitor of the conversion of dihydrofolic acid, which is necessary for the synthesis of nucleic acids and proteins. 42 The compound Kaempferol 3-rutinoside exhibits a high binding affinity value of -9.2 and shares similar residues with the control ligand. The control ligand, DQ0, forms hydrogen bonds with SER218, THR130, ASN108, SER111, GLY44, and THR107 and hydrophobic bonds with LEU127, and an ionic bond with ARG129 (Figure 4).…”