Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives

Muscia, Gisela Celeste; Cazorla, Silvia I.; Frank, Fernanda M.; Borosky, Gabriela L.; Buldain, Graciela; Asís, Sivlia E.; Malchiodi, Emilio L.

doi:10.1016/j.ejmech.2011.05.035

Cited by 32 publications

(29 citation statements)

References 36 publications

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“…The percent inhibition (%I) was calculated as %I ϭ {1 Ϫ [(CD 3t Ϫ CD 0 )/(CD 3c Ϫ CD 0 )]} ϫ 100, where CD 3t is the cellular density of treated parasites at day 3, CD 0 is the cellular density of parasites at day 0, and CD 3c is the cellular density of untreated parasites (control) at day 3. To evaluate the combinatory effect of B 12 and Bnz, the 50% inhibitory concentrations (IC 50 s) for Bnz in the presence of different B 12 concentrations (0.8 to 2.4 M) were calculated. The inhibitory activity of B 12 (0.25 M) was also evaluated in the presence of antioxidant agents such as dithiothreitol (DTT; 0.5 to 1 M) and vitamin C or ascorbic acid (0.5 to 1.5 M).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were infected with transfected trypomastigotes expressing ␤-galactosidase at a parasite/cell ratio of 10:1 as previously described (12). After 24 h of coculture, plates were washed to remove unbound parasites and drug compounds were added in duplicate.…”

Section: Methodsmentioning

confidence: 99%

“…Percent inhibition (%I) was calculated as 100 Ϫ {[(absorbance of treated infected cells Ϫ absorbance of treated uninfected cells)/(absorbance of untreated infected cells)] ϫ 100}, and the IC 50 was estimated. Because B 12 is colored and shows significant absorbance at 570 nm, blanks of uninfected cells with the different doses of B 12 were done and their absorbances were subtracted.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we have evaluated the in vitro antiparasitic activity of vitamin B 12 against different forms of T. cruzi, and we have explored its possible mode of action. Additionally, we have analyzed the interaction of B 12 with hemin and the improvement in activity by the addition of antioxidants.…”

mentioning

confidence: 99%

“…Additionally, we have analyzed the interaction of B 12 with hemin and the improvement in activity by the addition of antioxidants. More importantly, we have investigated the capacity of B 12 to control parasitemia in the murine model, showing its effect combined with Bnz treatment as a novel therapeutic modality.…”

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confidence: 99%

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Antiparasitic Effect of Vitamin B ₁₂ on Trypanosoma cruzi

Ciccarelli

Frank

Puente

et al. 2012

Antimicrob Agents Chemother

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A nutritional characteristic of trypanosomatid protozoa is that they need a heme compound as a growth factor. Because of the cytotoxic activity of heme and its structural similarity to cobalamins, we have investigated the in vitro and in vivo effect of vitamin B 12 (or cyanocobalamin) on the different forms of Trypanosoma cruzi. Cyanocobalamin showed a marked antiparasitic activity against epimastigotes (50% inhibitory concentration [IC 50 ], 2.42 M), amastigotes (IC 50 , 10.69 M), and trypomastigotes (IC 50 , 9.46 M). Anti-epimastigote and -trypomastigote values were 1.7 to 4 times lower than those obtained with the reference drug benznidazole (Bnz). We also found that B 12 and hemin do not interact with each other in their modes of action. Our results show that B 12 increases intracellular oxidative activity and stimulates both superoxide dismutase (50%) and ascorbate peroxidase (20%) activities, while the activity of trypanothione reductase was not modified. In addition, we found that the antioxidants dithiothreitol and ascorbic acid increase the susceptibility of the parasite to the cytotoxic action of B 12 . We propose that vitamin B 12 exerts its growth-inhibitory effect through the generation of reactive oxygen species. In an in vivo assay, a significant reduction in the number of circulating parasites was found in T. cruzi-infected mice treated with cyanocobalamin and ascorbic acid. The reduction of parasitemia in benznidazole-treated mice was improved by the addition of these vitamins. According to our results, a combination of B 12 and Bnz should be further investigated due to its potential as a new therapeutic modality for the treatment of Chagas' disease.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antiparasitic Effect of Vitamin B ₁₂ on Trypanosoma cruzi

Ciccarelli

Frank

Puente

et al. 2012

Antimicrob Agents Chemother

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Drug Design and Screening by In Silico Approaches

Mori

Botta

2013

Trypanosomatid Diseases

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Antiproliferative Evaluation of Some 2‐[2‐(2‐Phenylethenyl)‐cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles: DFT and Molecular Docking Study

Ceylan

Erkan

Yağlıoğlu

et al. 2020

Chemistry & Biodiversity

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The 2-[2-(2-phenylethenyl)cyclopent-3-en-1-yl]-1,3-benzothiazoles were synthesized from the reactions of 7benzylidenebicyclo[3.2.0]hept-2-en-6-ones with 2-aminobenzenethiol. The antiproliferative activities of 2-[2-(2phenylethenyl)cyclopent-3-en-1-yl]-1,3-benzothiazoles were determined against C6 (rat brain tumor) and HeLa (human cervical carcinoma cells) cell lines using BrdU cell proliferation ELISA assay. Cisplatin and 5-fluorouracil (5-FU) were used as standards. The most active compound was 2-{(1S,2S)-2-[(E)-2-(4-methylphenyl)ethenyl] cyclopent-3-en-1-yl}-1,3-benzothiazole against C6 cell lines with IC 50 = 5.89 μM value (cisplatin, IC 50 = 14.46 μM and 5-FU, IC 50 = 76.74 μM). Furthermore, the most active compound was 2-{(1S,2S)-2-[(E)-2-(2-methoxyphenyl) ethenyl]cyclopent-3-en-1-yl}-1,3-benzothiazole against HeLa cell lines with IC 50 = 3.98 μM (cisplatin, IC 50 = 37.95 μM and 5-FU, IC 50 = 46.32 μM). Additionally, computational studies of related molecules were performed by using B3LYP/6-31G + (d,p) level in the gas phase. Experimental IR and NMR data were compared with the calculated results and were found to be compatible with each other. Molecular electrostatic potential (MEP) maps of the most active 2-{(1S,2S)-2-[(E)-2-(2methoxyphenyl)ethenyl]cyclopent-3-en-1-yl}-1,3-benzothiazole against HeLa and the most active 2-{(1S,2S)-2-[(E)-2-(4-methylphenyl)ethenyl]cyclopent-3-en-1-yl}-1,3-benzothiazole against C6 were investigated, aiming to determine the region that the molecule is biologically active. Biological activities of mentioned molecules were investigated with molecular docking analyses. The appropriate target protein (PDB codes: 1 M17 for the HeLa cells and 1JQH for the C6 cells) was used for 2-{(1S,2S)-2-[(E)-2-(2-methoxyphenyl)ethenyl]cyclopent-3-en-1-yl}-1,3-benzothiazole and 2-{(1S,2S)-2-[(E)-2-(4-methylphenyl)ethenyl]cyclopent-3-en-1-yl}-1,3-benzothiazole molecules exhibiting the highest biological activity against HeLa and C6 cells in the docking studies. As a result, it was determined that these molecules are the best candidates for the anticancer drug. Figure 5. Interaction of molecule 5c (pink balls) with protein 1M17 and that of molecule 5e (red balls) with protein 1JQH.1 H-NMR (400 MHz, CDCl 3 ): 8.02 (d, J = 8.2, 1H), 7.87 (d, J = 7.8, 1H), 7.48 (ddd, J = 8.3, 7.2, 1.3, 2H), 7.43-7.31 (m, 4H), 7.06 -6.97 (m, 2H), 6.46 (d, J = 15.8, 1H), 6.22 (dd, J = 15.8, 8.0, 1H), 5.98 -5.92 (m, 1H), 5.82 -5.76 (m, 1H), 3.99 -3.87 (m, 1H), 3.77 (dt, J = 8.8, 7.3, 1H), 3.16 -3.03 (m, 1H), 3.00 -2.89 (m, 1H). 13 C-NMR (101 MHz,

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Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives

Cited by 32 publications

References 36 publications

Antiparasitic Effect of Vitamin B ₁₂ on Trypanosoma cruzi

Antiparasitic Effect of Vitamin B ₁₂ on Trypanosoma cruzi

Drug Design and Screening by In Silico Approaches

Antiproliferative Evaluation of Some 2‐[2‐(2‐Phenylethenyl)‐cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles: DFT and Molecular Docking Study

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Synthesis, trypanocidal activity and molecular modeling studies of 2-alkylaminomethylquinoline derivatives

Cited by 32 publications

References 36 publications

Antiparasitic Effect of Vitamin B 12 on Trypanosoma cruzi

Antiparasitic Effect of Vitamin B 12 on Trypanosoma cruzi

Drug Design and Screening by In Silico Approaches

Antiproliferative Evaluation of Some 2‐[2‐(2‐Phenylethenyl)‐cyclopent‐3‐en‐1‐yl]‐1,3‐benzothiazoles: DFT and Molecular Docking Study

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Antiparasitic Effect of Vitamin B ₁₂ on Trypanosoma cruzi

Antiparasitic Effect of Vitamin B ₁₂ on Trypanosoma cruzi