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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

Comparison between the distance of heme-chelator group and the first carbon in C–C linker in both miconazole and compound V.Notes: (A) Measuring the distance between the C–C linker and heme chelator group in Miconazole. (B) Measuring the distance between the C–C linker and heme chelator group in the compound V.
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f12-dddt-9-4501: Comparison between the distance of heme-chelator group and the first carbon in C–C linker in both miconazole and compound V.Notes: (A) Measuring the distance between the C–C linker and heme chelator group in Miconazole. (B) Measuring the distance between the C–C linker and heme chelator group in the compound V.

Mentions: When measuring the distance between N3 of imidazole and the first carbon in the C–C linker, it was found to be 3.55 Å. Conversely, in the case of compound V, the distance between the oxygen atom and the C=C linker was 2.4 Å. This finding can introduce a new structural feature for the design of a potent antifungal drug (Figure 12).


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)

Comparison between the distance of heme-chelator group and the first carbon in C–C linker in both miconazole and compound V.Notes: (A) Measuring the distance between the C–C linker and heme chelator group in Miconazole. (B) Measuring the distance between the C–C linker and heme chelator group in the compound V.
© Copyright Policy
Related In: Results  -  Collection

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

f12-dddt-9-4501: Comparison between the distance of heme-chelator group and the first carbon in C–C linker in both miconazole and compound V.Notes: (A) Measuring the distance between the C–C linker and heme chelator group in Miconazole. (B) Measuring the distance between the C–C linker and heme chelator group in the compound V.
Mentions: When measuring the distance between N3 of imidazole and the first carbon in the C–C linker, it was found to be 3.55 Å. Conversely, in the case of compound V, the distance between the oxygen atom and the C=C linker was 2.4 Å. This finding can introduce a new structural feature for the design of a potent antifungal drug (Figure 12).

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