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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

(A) Chemical structure of the first 1-phenethyl imidazole scaffold. (B) General structure of azole antifungal drugs.
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f3-dddt-9-4501: (A) Chemical structure of the first 1-phenethyl imidazole scaffold. (B) General structure of azole antifungal drugs.

Mentions: The first discovery of azole drugs was after the in vitro screening of 1-phenethyl imidazole derivatives (Figure 3A) against a large number of fungal species. They revealed broad-spectrum antifungal activity. Since then, this scaffold was used to develop more potent antifungal agents.16 Further modifications of the 1-phenethyl imidazole scaffold resulted in the common structure of azole antifungal drugs (Figure 3B). They share common structural features like the azole heme-coordinating group, a halo-substituted aromatic ring that is separated by two carbon atoms from the azole moiety, and a hydrophobic side chain that may be a halo-substituted aromatic ring as well. Most of the well-known antifungal drugs share these common structural features (Figure 4).


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)

(A) Chemical structure of the first 1-phenethyl imidazole scaffold. (B) General structure of azole antifungal drugs.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-9-4501: (A) Chemical structure of the first 1-phenethyl imidazole scaffold. (B) General structure of azole antifungal drugs.
Mentions: The first discovery of azole drugs was after the in vitro screening of 1-phenethyl imidazole derivatives (Figure 3A) against a large number of fungal species. They revealed broad-spectrum antifungal activity. Since then, this scaffold was used to develop more potent antifungal agents.16 Further modifications of the 1-phenethyl imidazole scaffold resulted in the common structure of azole antifungal drugs (Figure 3B). They share common structural features like the azole heme-coordinating group, a halo-substituted aromatic ring that is separated by two carbon atoms from the azole moiety, and a hydrophobic side chain that may be a halo-substituted aromatic ring as well. Most of the well-known antifungal drugs share these common structural features (Figure 4).

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