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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

Possible binding modes of the designed compounds within the Candida albicans L14αDM homology model.
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f2-dddt-9-4501: Possible binding modes of the designed compounds within the Candida albicans L14αDM homology model.

Mentions: All compounds were built and saved as mol2 files. The homology model of C. albicans L14α-DM was used for docking. The protein was loaded into Leadit 2.1.2 and the receptor components were chosen by selection of chain A as a main chain, which is complexed with heme–porphyrin and azole inhibitor. Binding site was defined by choosing azole inhibitor as a reference ligand to which all coordinates were computed. Amino acids within a radius of 6.5 Å were selected in the binding site. All chemical ambiguities of residues were left as default. Ligand binding was driven by enthalpy (classic Triangle matching). For scoring, all default settings were restored. Intraligand clashes were computed by using clash factor =0.6. Maximum number of solutions per iteration =200. Maximum number of solution per fragmentation =200. The base placement method was used as a docking strategy. Docking results are tabulated 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)

Possible binding modes of the designed compounds within the Candida albicans L14αDM homology model.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-9-4501: Possible binding modes of the designed compounds within the Candida albicans L14αDM homology model.
Mentions: All compounds were built and saved as mol2 files. The homology model of C. albicans L14α-DM was used for docking. The protein was loaded into Leadit 2.1.2 and the receptor components were chosen by selection of chain A as a main chain, which is complexed with heme–porphyrin and azole inhibitor. Binding site was defined by choosing azole inhibitor as a reference ligand to which all coordinates were computed. Amino acids within a radius of 6.5 Å were selected in the binding site. All chemical ambiguities of residues were left as default. Ligand binding was driven by enthalpy (classic Triangle matching). For scoring, all default settings were restored. Intraligand clashes were computed by using clash factor =0.6. Maximum number of solutions per iteration =200. Maximum number of solution per fragmentation =200. The base placement method was used as a docking strategy. Docking results are tabulated 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