Multicomponent synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives.

Herein, we report a one-pot greener methodology for the synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives by the multicomponent reaction of arylglyoxal monohydrate, 2-amino-1,4-naphthoquinone, and indole in acetonitrile medium under reflux conditions in the presence of 10 mol% sulfamic acid as a catalyst in 20-30 min of reaction time. Three new bonds have formed (2 C-C, 1 C-N) in this methodology. Bioactive moieties such as indole, pyrrole and naphthoquinone are present in our product. This methodology is also applicable in gram-scale synthesis. A wide variety of substrates were tested to find the generality of the methodology and good yield of the products were obtained in a very short reaction time. Along with the operational simplicity of the methodology, purification process of the products is easier by simple recrystallization process. All the synthesized products were characterized by spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, and HRMS.

Biological activity of 1,2,3-triazole-2-amino-1,4-naphthoquinone derivatives and their evaluation as therapeutic strategy for malaria control.

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 µM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 µM. Compounds 7, 8 and 11 showed IC50 values < 5 µM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.

1H and 13C NMR chemical shifts of 2-n-alkylamino-naphthalene-1,4-diones.

1H as well as 13C chemical shifts of 32 compounds of C (3) substituted 2-(n-alkylamino)-3R-naphthalene-1,4-dione (where n-alkyl: methyl, to octyl, R = H, Cl, Br, and CH3) are investigated through 1H, 13C, DEPT, gDQCOSY, and gHSQCAD NMR experiments and M06-2X/6-311++G (d,p) density functional theory are discussed. Single crystal X-ray structure of Br-3, as well as 18 different derivatives of naphthalene-1,4-diones, are revealed for its inter and intra-molecular hydrogen bonding interactions.

In Vitro Analysis of the Combinatory Effects of Novel Aminonaphthoquinone Derivatives and Curcumin on Breast Cancer Progression.

BACKGROUND/AIM: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells. MATERIALS AND METHODS: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel. RESULTS: Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations. CONCLUSION: Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.

Evaluation of the Effects of Aminonaphthoquinone Derivatives in Combination with Curcumin Against ER-positive Breast Cancer and Related Tumours.

BACKGROUND/AIM: Combination therapies are often explored to treat cancer. The use of curcumin as an adjuvant to current chemotherapies has been reported, whilst aminonaphthoquinones have shown potential as anticancer agents in various tumour cell lines. This study aimed at screening synthetic aminonathoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) alone and in combination with curcumin for anti-breast cancer activity. MATERIALS AND METHODS: Combination effects were determined in MCF-7 breast cancer cells using combination index analyses. Synergistic anti-proliferative effects were further investigated in breast (MCF-7, MDA-MB-231), osteosarcoma (MG-63) and endometrial (HEC-1A) cancer-derived cells. RESULTS: Rau 015 (15 µM) and curcumin (112.5 µM) significantly reduced MCF-7, MDA-MB-231 and MG-63 cell proliferation compared to individual treatment, indicating synergistic anti-proliferative effects. Rau 018 (30 µM) and curcumin (100 µM) displayed similar effects in MCF-7 and MG-63 cells. CONCLUSION: We report on the potential of Rau 015 or Rau 018 as anti-breast cancer agents when combined with curcumin.

Copper-catalyzed three-component synthesis of aminonaphthoquinone-sulfonylamidine conjugates and in vitro evaluation of their antiproliferative activity.

A series of aminonaphthoquinone-sulfonylamidine conjugates were synthesized via a copper-catalyzed three-component reaction of N-propargyl aminonaphthoquinone, sulfonyl azides and various amines. Majority of the compounds exhibited promising antiproliferative potential when evaluated against a panel of four cancer cell lines. Docking experiments of representative compounds indicated that the conjugates can occupy the ATP-binding pocket of topoisomerase-II enzyme.