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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

Effect of metronidazole (MTZ) and compound 65 on Giardia trophozoites. Dose-response curves of MTZ (A) and the newly synthesized compound 65(B), measured on Giardia trophozoites cultured under anaerobic (closed symbol) or microaerobic (open symbol) conditions. Data are expressed as mean ± SEM (n ≥ 6).
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Figure 2: Effect of metronidazole (MTZ) and compound 65 on Giardia trophozoites. Dose-response curves of MTZ (A) and the newly synthesized compound 65(B), measured on Giardia trophozoites cultured under anaerobic (closed symbol) or microaerobic (open symbol) conditions. Data are expressed as mean ± SEM (n ≥ 6).

Mentions: The antigiardial activity of the novel compounds 23–67 was tested under both anaerobic and microaerobic conditions. According to (Dunn et al., 2010; Bahadur et al., 2014), susceptibility of Giardia trophozoites to increasing concentrations of each compound was assessed based on ATP level determination by luminescence. Dose-response curves for each compound were obtained after 48 h-incubation and compared to the data collected under identical conditions with MTZ, the drug of choice for treatment of giardiasis. In these assays, the ATP level measured in control Giardia trophozoites grown under microaerobic conditions was found to be approximately 25% lower than in the same cells grown under anaerobic conditions, and DMSO at concentrations ≤2%v/v caused only marginal effects on cell ATP levels. Typical dose-response curves are shown in Figure 2, whereas the IC50 values measured for the synthetic compounds and MTZ under anaerobic and microaerobic conditions are reported in Table 1. In agreement with the literature (Müller et al., 2006), under the experimental conditions of the assay, MTZ proved to be highly effective (IC50 = 3.4 μM) against Giardia parasites in the absence of O2, but remarkably less (IC50 ≥ 25 μM) under microaerobic conditions. Under anaerobic conditions, 18 out of the 45 synthetic compounds were as effective as MTZ or more under identical conditions (see Table 1). Among them, compounds 41, 43, and 45 displayed the highest activity, being three to fourfold more efficient than MTZ.


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)

Effect of metronidazole (MTZ) and compound 65 on Giardia trophozoites. Dose-response curves of MTZ (A) and the newly synthesized compound 65(B), measured on Giardia trophozoites cultured under anaerobic (closed symbol) or microaerobic (open symbol) conditions. Data are expressed as mean ± SEM (n ≥ 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Effect of metronidazole (MTZ) and compound 65 on Giardia trophozoites. Dose-response curves of MTZ (A) and the newly synthesized compound 65(B), measured on Giardia trophozoites cultured under anaerobic (closed symbol) or microaerobic (open symbol) conditions. Data are expressed as mean ± SEM (n ≥ 6).
Mentions: The antigiardial activity of the novel compounds 23–67 was tested under both anaerobic and microaerobic conditions. According to (Dunn et al., 2010; Bahadur et al., 2014), susceptibility of Giardia trophozoites to increasing concentrations of each compound was assessed based on ATP level determination by luminescence. Dose-response curves for each compound were obtained after 48 h-incubation and compared to the data collected under identical conditions with MTZ, the drug of choice for treatment of giardiasis. In these assays, the ATP level measured in control Giardia trophozoites grown under microaerobic conditions was found to be approximately 25% lower than in the same cells grown under anaerobic conditions, and DMSO at concentrations ≤2%v/v caused only marginal effects on cell ATP levels. Typical dose-response curves are shown in Figure 2, whereas the IC50 values measured for the synthetic compounds and MTZ under anaerobic and microaerobic conditions are reported in Table 1. In agreement with the literature (Müller et al., 2006), under the experimental conditions of the assay, MTZ proved to be highly effective (IC50 = 3.4 μM) against Giardia parasites in the absence of O2, but remarkably less (IC50 ≥ 25 μM) under microaerobic conditions. Under anaerobic conditions, 18 out of the 45 synthetic compounds were as effective as MTZ or more under identical conditions (see Table 1). Among them, compounds 41, 43, and 45 displayed the highest activity, being three to fourfold more efficient than MTZ.

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