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Antigiardial activity of novel triazolyl-quinolone-based chalcone derivatives: when oxygen makes the difference.

Bahadur V, Mastronicola D, Singh AK, Tiwari HK, Pucillo LP, Sarti P, Singh BK, Giuffrè A - Front Microbiol (2015)

Bottom Line: New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective.All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective.Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions.

View Article: PubMed Central - PubMed

Affiliation: Bio-Organic Laboratory, Department of Chemistry, University of Delhi Delhi, India.

ABSTRACT
Giardiasis is a common diarrheal disease worldwide caused by the protozoan parasite Giardia intestinalis. It is urgent to develop novel drugs to treat giardiasis, due to increasing clinical resistance to the gold standard drug metronidazole (MTZ). New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective. On the other hand, though commonly regarded as an 'anaerobic pathogen,' G. intestinalis is exposed to relatively high O2 levels in vivo, living attached to the mucosa of the proximal small intestine. It is thus important to test the effect of O2 when searching for novel potential antigiardial agents, as outlined in a previous study [Bahadur et al. (2014) Antimicrob. Agents Chemother. 58, 543]. Here, 45 novel chalcone derivatives with triazolyl-quinolone scaffold were synthesized, purified, and characterized by high resolution mass spectrometry, (1)H and (13)C nuclear magnetic resonance and infrared spectroscopy. Efficacy of the compounds against G. intestinalis trophozoites was tested under both anaerobic and microaerobic conditions, and selectivity was assessed in a counter-screen on human epithelial colorectal adenocarcinoma cells. MTZ was used as a positive control in the assays. All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective. Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions. Four of them represent potential candidates for the design of novel antigiardial drugs, being highly selective against Giardia trophozoites. This study further underlines the importance of taking O2 into account when testing novel potential antigiardial compounds.

No MeSH data available.


Related in: MedlinePlus

Synthetic route to compounds 23–67. (a) DMF, POCl3, 0–100∘C, 16 h; (b) 70% acetic acid, 110∘C, 12 h; (c) K2CO3, DMF, rt, 12 h; (d) CuSO4⋅5H2O, Na-ascorbate, THF:H2O (3:1), rt, 12 h; (e) NaOH, MeOH, rt, 24 h.
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Figure 1: Synthetic route to compounds 23–67. (a) DMF, POCl3, 0–100∘C, 16 h; (b) 70% acetic acid, 110∘C, 12 h; (c) K2CO3, DMF, rt, 12 h; (d) CuSO4⋅5H2O, Na-ascorbate, THF:H2O (3:1), rt, 12 h; (e) NaOH, MeOH, rt, 24 h.

Mentions: Forty-five novel triazolyl-quinolone-based chalcone derivatives were synthesized based on previously described Claisen-Schmidt condensation (Li et al., 1995), according to the synthetic route outlined in Figure 1. Intermediate triazolyl-quinolone compounds 10–14 were synthesized at room temperature in THF:water with 50–75% yield, by “click chemistry” (Barral et al., 2007) of the synthesized alkyne 4 with appropriate aromatic azides (5–9), using CuSO4⋅5H2O and sodium ascorbate as catalysts. As shown in Figure 1, compounds 23–67 were obtained at room temperature by reaction of the intermediate compounds 10–14 with commercially available aromatic acetophenones 15–22, in the presence of NaOH in dry MeOH. After purification, the yield of products 23–67 ranged from 60 to 95%.


Antigiardial activity of novel triazolyl-quinolone-based chalcone derivatives: when oxygen makes the difference.

Bahadur V, Mastronicola D, Singh AK, Tiwari HK, Pucillo LP, Sarti P, Singh BK, Giuffrè A - Front Microbiol (2015)

Synthetic route to compounds 23–67. (a) DMF, POCl3, 0–100∘C, 16 h; (b) 70% acetic acid, 110∘C, 12 h; (c) K2CO3, DMF, rt, 12 h; (d) CuSO4⋅5H2O, Na-ascorbate, THF:H2O (3:1), rt, 12 h; (e) NaOH, MeOH, rt, 24 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389562&req=5

Figure 1: Synthetic route to compounds 23–67. (a) DMF, POCl3, 0–100∘C, 16 h; (b) 70% acetic acid, 110∘C, 12 h; (c) K2CO3, DMF, rt, 12 h; (d) CuSO4⋅5H2O, Na-ascorbate, THF:H2O (3:1), rt, 12 h; (e) NaOH, MeOH, rt, 24 h.
Mentions: Forty-five novel triazolyl-quinolone-based chalcone derivatives were synthesized based on previously described Claisen-Schmidt condensation (Li et al., 1995), according to the synthetic route outlined in Figure 1. Intermediate triazolyl-quinolone compounds 10–14 were synthesized at room temperature in THF:water with 50–75% yield, by “click chemistry” (Barral et al., 2007) of the synthesized alkyne 4 with appropriate aromatic azides (5–9), using CuSO4⋅5H2O and sodium ascorbate as catalysts. As shown in Figure 1, compounds 23–67 were obtained at room temperature by reaction of the intermediate compounds 10–14 with commercially available aromatic acetophenones 15–22, in the presence of NaOH in dry MeOH. After purification, the yield of products 23–67 ranged from 60 to 95%.

Bottom Line: New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective.All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective.Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions.

View Article: PubMed Central - PubMed

Affiliation: Bio-Organic Laboratory, Department of Chemistry, University of Delhi Delhi, India.

ABSTRACT
Giardiasis is a common diarrheal disease worldwide caused by the protozoan parasite Giardia intestinalis. It is urgent to develop novel drugs to treat giardiasis, due to increasing clinical resistance to the gold standard drug metronidazole (MTZ). New potential antiparasitic compounds are usually tested for their killing efficacy against G. intestinalis under anaerobic conditions, in which MTZ is maximally effective. On the other hand, though commonly regarded as an 'anaerobic pathogen,' G. intestinalis is exposed to relatively high O2 levels in vivo, living attached to the mucosa of the proximal small intestine. It is thus important to test the effect of O2 when searching for novel potential antigiardial agents, as outlined in a previous study [Bahadur et al. (2014) Antimicrob. Agents Chemother. 58, 543]. Here, 45 novel chalcone derivatives with triazolyl-quinolone scaffold were synthesized, purified, and characterized by high resolution mass spectrometry, (1)H and (13)C nuclear magnetic resonance and infrared spectroscopy. Efficacy of the compounds against G. intestinalis trophozoites was tested under both anaerobic and microaerobic conditions, and selectivity was assessed in a counter-screen on human epithelial colorectal adenocarcinoma cells. MTZ was used as a positive control in the assays. All the tested compounds proved to be more effective against the parasite in the presence of O2, with the exception of MTZ that was less effective. Under anaerobiosis eighteen compounds were found to be as effective as MTZ or more (up to three to fourfold); the same compounds proved to be up to >100-fold more effective than MTZ under microaerobic conditions. Four of them represent potential candidates for the design of novel antigiardial drugs, being highly selective against Giardia trophozoites. This study further underlines the importance of taking O2 into account when testing novel potential antigiardial compounds.

No MeSH data available.


Related in: MedlinePlus