Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity.

Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents. 19 is the only compound of the series showing a balanced dual profile at 10 µM (% inhibitionTbGAPDH = 64% and % inhibitionTcTR = 65%). In phenotypic assay, the most active compounds were 18 and 21, which at 5 µM inhibited Tb bloodstream-form growth by 29% and 38%, respectively. Notably, all the newly synthesized compounds at 10 µM did not affect viability and the status of mitochondria in human A549 and 786-O cell lines, respectively. However, further optimization that addresses metabolic liabilities including solubility, as well as cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, and CYP2D6) inhibition, is required before this class of natural product-derived compounds can be further progressed.

Cytotoxic activity of naphthoquinones with special emphasis on juglone and its 5-O-methyl derivative.

The cytotoxicity of nine naphthoquinones (NQ) was assayed against HL-60 (leukaemia), MDA-MB-435 (melanoma), SF-295 (brain) and HCT-8 (colon), all human cancer cell lines, and peripheral blood mononuclear cells (PBMC), as representatives of normal cells, after 72h of incubation. 5-Methoxy-1,4-naphthoquinone was the most active compound, showing IC(50) values in the range of 0.31 (1.7microM) in HL-60 to 0.88microg/mL (4.7microM) in SF-295 and IC(50) of 0.69microg/mL (3.7microM) against PBMC. With the introduction of a bromo-substituent in position 2 or 3 of juglone, the IC(50) significantly decreased, regardless of the position on the NQ moiety. However, compared with juglone methyl ether, the halogen substitution decreased the activity. To further understand the mechanism underlying the cytotoxicity of 5-methoxy-1,4-naphthoquinone, studies involving DNA fragmentation, cell cycle analysis, phosphatidyl serine externalization, mitochondrial depolarization and activation of caspases 8 and 3/7 were performed in HL-60 cell line, using doxorubicin as a positive control. The results indicate that the cytotoxic 5-methoxy-1,4-naphthoquinone activates caspases 8 and 3/7 and thus induces apoptosis independent of mitochondria.

Activities of naphthoquinones against Aedes aegypti (Linnaeus, 1762) (Diptera: Culicidae), vector of dengue and Biomphalaria glabrata (Say, 1818), intermediate host of Schistosoma mansoni.

Larvicidal (against Aedes aegypti Linnaeus, 1762) and molluscicidal (against Biomphalaria glabrata Say, 1818) activities of several natural and synthetic naphthoquinones were measured, with significant results. The best larvicidal compound is 3-bromojuglone, while the better molluscicides are 2-bromo- and 3-bromo-5-acetoxy-1,4-naphthoquinones together with the 3-bromo-5-methoxy derivative. The present results reinforce the potential use of substituted hydroxyquinones, their salts and halogenated quinones as very promising compounds against 4th instar larves of Aedes aegypti, the vector of dengue and against adult snail of Biomphalaria glabrata.