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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

The similar residues are in grey color, hydrophobic residues in blue color, and the metal binding site at position 470 of in template and query.
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f7-dddt-9-4501: The similar residues are in grey color, hydrophobic residues in blue color, and the metal binding site at position 470 of in template and query.

Mentions: Unfortunately, the crystal structure of L14αDM for C. albicans and most of the fungal species are not available. Many studies reported the homology model of C. albicans L14αDM.27 However, in all previously reported models, the template that was used was from Mycobacterium tuberculosis, and it shared a low percentage of identity with the query sequence. Recently, the crystal structure of S. cerevisiae L14αDM (PDB entry code 4LXJ) was resolved;28 the sequence alignment of both C. albicans and S. cerevisiae L14αDM appeared to share 62.82% identity (Figure 7). In this work, a homology model of C. albicans L14αDM was built in order to predict the orientation and binding of the designed compounds to heme within the active site, as compared to miconazole and fluconazole.


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)

The similar residues are in grey color, hydrophobic residues in blue color, and the metal binding site at position 470 of in template and query.
© Copyright Policy
Related In: Results  -  Collection

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

f7-dddt-9-4501: The similar residues are in grey color, hydrophobic residues in blue color, and the metal binding site at position 470 of in template and query.
Mentions: Unfortunately, the crystal structure of L14αDM for C. albicans and most of the fungal species are not available. Many studies reported the homology model of C. albicans L14αDM.27 However, in all previously reported models, the template that was used was from Mycobacterium tuberculosis, and it shared a low percentage of identity with the query sequence. Recently, the crystal structure of S. cerevisiae L14αDM (PDB entry code 4LXJ) was resolved;28 the sequence alignment of both C. albicans and S. cerevisiae L14αDM appeared to share 62.82% identity (Figure 7). In this work, a homology model of C. albicans L14αDM was built in order to predict the orientation and binding of the designed compounds to heme within the active site, as compared to miconazole and fluconazole.

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