In Vitro and In Silico Potential Inhibitory Effects of New Biflavonoids from Ochna rhizomatosa on HIV-1 Integrase and Plasmodium falciparum

Abstract

The aim of this study was to identify bioactive secondary metabolites from Ochna rhizomatosa with potential inhibitory effects against HIV and Plasmodium falciparum. A phytochemical study of O. rhizomatosa root barks resulted in the identification of three new biflavonoids (1-3), along with four known ones (4-7). Compound 7 (Gerontoisoflavone A) was a single flavonoid present in the rootbark of the plant and was used as a reference. Compound 1 (IC₅₀ = 0.047 µM) was the only one with a noteworthy inhibitory effect against HIV-1 integrase in vitro. Chicoric acid (IC₅₀ = 0.006 µM), a pure competitive inhibitor of HIV-1 integrase, was used as control. Compound 2 exhibited the highest antiplasmodial activity (IC₅₀ = 4.60 µM) against the chloroquine-sensitive strain of Plasmodium falciparum NF54. Computational molecular docking revealed that compounds 1 and 2 had the highest binding score (-121.8 and -131.88 Kcal/mol, respectively) in comparison to chicoric acid and Dolutegravir (-116 and -100 Kcal/mol, respectively), towards integrase receptor (PDB:3LPT). As far as Plasmodium-6 cysteine s48/45 domain inhibition is concerned, compounds 1 and 2 showed the highest binding scores in comparison to chloroquine, urging the analysis of these compounds in vivo for disease treatment. These results confirm the potential inhibitory effect of compounds 1 and 2 for HIV and malaria treatment. Therefore, our future investigation to find inhibitors of these receptors in vivo could be an effective strategy for developing new drugs.

Keywords: HIV-1 replication; Ochna rhizomatosa; Plasmodium falciparum NF54; biflavonoids; molecular docking; structure–activity relationships.

Figure 1

Chemical structures of the isolated compounds (1–7) from the root bark of Ochna rhizomatosa.

Figure 1

Chemical structures of the isolated compounds (1–7) from the root bark of Ochna rhizomatosa.

Figure 2

Key HMBC and ROESY correlations of (1–3).

Figure 3

Structure–activity relationships established for anti-HIV-1 effect against the inhibition of the protein integrase of compounds (1) and (2). Red colors express hydroxyl groups and blue colors express methoxyl groups.

Figure 4

Structure–activity relationships established for antiplasmodial effect against chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum NF54 of compounds (1), (2) and (7).

Figure 5

Summary of the most relevant structure–activity relationships established by compounds (1), (2) and (7).

Figure 6

Interaction of compounds 1, 2, 7, Dolutegravir and chicoric acid with integrase protein (PDB ID: 3LPT). Compound 1: (R) rhizomatobiflavonoid A; Compound 2: (R) rhizomatobiflavonoid B; Compound 7: Gerontoisoflavone A. Int: integrase receptor.

Figure 6

Interaction of compounds 1, 2, 7, Dolutegravir and chicoric acid with integrase protein (PDB ID: 3LPT). Compound 1: (R) rhizomatobiflavonoid A; Compound 2: (R) rhizomatobiflavonoid B; Compound 7: Gerontoisoflavone A. Int: integrase receptor.

Figure 6

Interaction of compounds 1, 2, 7, Dolutegravir and chicoric acid with integrase protein (PDB ID: 3LPT). Compound 1: (R) rhizomatobiflavonoid A; Compound 2: (R) rhizomatobiflavonoid B; Compound 7: Gerontoisoflavone A. Int: integrase receptor.

Figure 7

Interaction of compounds 1, 2, 7 and chloroquine with active cavities of Plasmodium falciparum protein receptor, PDB ID: 2LOE. Compound 1: (R) rhizomatobiflavonoid A; Compound 2: (R) rhizomatobiflavonoid B; Compound 7: Gerontoisoflavone A. Plasm: Plasmodium receptor.

Figure 7

Interaction of compounds 1, 2, 7 and chloroquine with active cavities of Plasmodium falciparum protein receptor, PDB ID: 2LOE. Compound 1: (R) rhizomatobiflavonoid A; Compound 2: (R) rhizomatobiflavonoid B; Compound 7: Gerontoisoflavone A. Plasm: Plasmodium receptor.