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Stepwise design, synthesis, and in vitro antifungal screening of (Z)-substituted-propenoic acid derivatives with potent broad-spectrum antifungal activity.

Khedr MA - Drug Des Devel Ther (2015)

Bottom Line: In silico study results showed the high binding affinity to lanosterol 14α-demethylase (-24.49 and -25.83 kcal/mol) for compounds V and VII, respectively; these values were greater than those for miconazole (-18.19 kcal/mol) and fluconazole (-16.08 kcal/mol).Compound V emerged as the most potent antifungal agent among all compounds with a half maximal inhibitory concentration of 7.01, 7.59, 7.25, 31.6, and 41.6 µg/mL against Candida albicans, Candida parapsilosis, Aspergillus niger, Trichophyton rubrum, and Trichophyton mentagrophytes, respectively.The antifungal activity for most of the synthesized compounds was more potent than that of miconazole and fluconazole.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.

ABSTRACT
Fungal infections are a main reason for the high mortality rate worldwide. It is a challenge to design selective antifungal agents with broad-spectrum activity. Lanosterol 14α-demethylase is an attractive target in the design of antifungal agents. Seven compounds were selected from a number of designed compounds using a rational docking study. These compounds were synthesized and evaluated for their antifungal activity. In silico study results showed the high binding affinity to lanosterol 14α-demethylase (-24.49 and -25.83 kcal/mol) for compounds V and VII, respectively; these values were greater than those for miconazole (-18.19 kcal/mol) and fluconazole (-16.08 kcal/mol). Compound V emerged as the most potent antifungal agent among all compounds with a half maximal inhibitory concentration of 7.01, 7.59, 7.25, 31.6, and 41.6 µg/mL against Candida albicans, Candida parapsilosis, Aspergillus niger, Trichophyton rubrum, and Trichophyton mentagrophytes, respectively. The antifungal activity for most of the synthesized compounds was more potent than that of miconazole and fluconazole.

No MeSH data available.


Related in: MedlinePlus

Mode of binding of compound V in the azole binding site of L14αDM.
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f10-dddt-9-4501: Mode of binding of compound V in the azole binding site of L14αDM.

Mentions: The higher value of the ligand entropy conformation score in both miconazole and fluconazole was inversely proportional to the binding affinity. The best value for the lipophilic contribution was found to be −12.60 and −12.44 for the most active compounds (VII and V, respectively). By analysis of the interactions, we can conclude that the Z-configuration of the synthesized compounds was successful in enabling the carboxylic group to chelate with the heme in the heme–porphyrin complex. The 2,4-dichloro phenoxy moiety in all compounds, in addition to the halo and/or an electron-withdrawing aromatic substituted rings, resulted in an electron-poor phenyl ring, and that was the cause of π–π interactions with neighboring hydrophobic residues such as Tyr 126, Tyr 140, Phe 134, Phe 241, and Phe 236. The presence of the para nitro group in compounds V and VII showed an extra hydrogen bond with Thr 130 (Figure 10). The possible binding mode for the top selected compounds is summarized in Figure 2.


Stepwise design, synthesis, and in vitro antifungal screening of (Z)-substituted-propenoic acid derivatives with potent broad-spectrum antifungal activity.

Khedr MA - Drug Des Devel Ther (2015)

Mode of binding of compound V in the azole binding site of L14αDM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539092&req=5

f10-dddt-9-4501: Mode of binding of compound V in the azole binding site of L14αDM.
Mentions: The higher value of the ligand entropy conformation score in both miconazole and fluconazole was inversely proportional to the binding affinity. The best value for the lipophilic contribution was found to be −12.60 and −12.44 for the most active compounds (VII and V, respectively). By analysis of the interactions, we can conclude that the Z-configuration of the synthesized compounds was successful in enabling the carboxylic group to chelate with the heme in the heme–porphyrin complex. The 2,4-dichloro phenoxy moiety in all compounds, in addition to the halo and/or an electron-withdrawing aromatic substituted rings, resulted in an electron-poor phenyl ring, and that was the cause of π–π interactions with neighboring hydrophobic residues such as Tyr 126, Tyr 140, Phe 134, Phe 241, and Phe 236. The presence of the para nitro group in compounds V and VII showed an extra hydrogen bond with Thr 130 (Figure 10). The possible binding mode for the top selected compounds is summarized in Figure 2.

Bottom Line: In silico study results showed the high binding affinity to lanosterol 14α-demethylase (-24.49 and -25.83 kcal/mol) for compounds V and VII, respectively; these values were greater than those for miconazole (-18.19 kcal/mol) and fluconazole (-16.08 kcal/mol).Compound V emerged as the most potent antifungal agent among all compounds with a half maximal inhibitory concentration of 7.01, 7.59, 7.25, 31.6, and 41.6 µg/mL against Candida albicans, Candida parapsilosis, Aspergillus niger, Trichophyton rubrum, and Trichophyton mentagrophytes, respectively.The antifungal activity for most of the synthesized compounds was more potent than that of miconazole and fluconazole.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt.

ABSTRACT
Fungal infections are a main reason for the high mortality rate worldwide. It is a challenge to design selective antifungal agents with broad-spectrum activity. Lanosterol 14α-demethylase is an attractive target in the design of antifungal agents. Seven compounds were selected from a number of designed compounds using a rational docking study. These compounds were synthesized and evaluated for their antifungal activity. In silico study results showed the high binding affinity to lanosterol 14α-demethylase (-24.49 and -25.83 kcal/mol) for compounds V and VII, respectively; these values were greater than those for miconazole (-18.19 kcal/mol) and fluconazole (-16.08 kcal/mol). Compound V emerged as the most potent antifungal agent among all compounds with a half maximal inhibitory concentration of 7.01, 7.59, 7.25, 31.6, and 41.6 µg/mL against Candida albicans, Candida parapsilosis, Aspergillus niger, Trichophyton rubrum, and Trichophyton mentagrophytes, respectively. The antifungal activity for most of the synthesized compounds was more potent than that of miconazole and fluconazole.

No MeSH data available.


Related in: MedlinePlus