Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections.

A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 µg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 µg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.

Rapid and sensitive screening of antifungal activity in medicinal plants by a single-cell biosensing system.

A biosensing system based on the response of fungal cells was used for the evaluation of antifungal activity of medicinal plants against Aspergillus niger. This system measured the hyphal growth rate in real time in the presence or absence of Chinese herbal extracts. The sensitivity of this system was 100-fold higher than that of conventional methods, and is advisable for the screening of antifungal compounds.

Treatment of mycoses in cancer patients.

Invasive fungal infections are becoming increasingly frequent among immunocompromised patients and especially among cancer patients. The most common pathogens identified are Candida species, Aspergillus species, Cryptococcus neoformans, and Mucor species. Amphotericin B remains the mainstay of antifungal therapy. However, the toxicity of this drug may limit its use and, in addition, both failures and relapses have been reported. 5-Fluorocytosine and imidazoles, such as miconazole and ketoconazole, have been shown to be active, mainly on yeast organisms. The emergence of 5-fluorocytosine-resistant strains warrants caution for its administration as a single agent. The specific role of ketoconazole has not yet been established in large studies. In our experience, ketoconazole seems to be effective in the treatment of severe oral candidiasis in non-neutropenic cancer patients. Moreover, ketoconazole administered prophylactically to neutropenic patients decreases the number of positive surveillance cultures in these patients. The rare incidence of major toxicity and the ability to administer ketoconazole orally represent also major arguments for further investigation of ketoconazole activity by prospective controlled studies.

Treatment of experimental murine cryptococcosis: a comparison of miconazole and amphotericin B.

Miconazole was compared with amphotericin B in the treatment of murine cryptococcosis. Both subcutaneous and intraperitoneal administration of miconazole produced serum levels higher than the minimum inhibitory concentration for the challenge strain. However, maximal tolerable doses of miconazole gave no increase in survival. When combined with amphotericin B, miconazole demonstrated neither additive nor antagonistic effects on survival. Spleen and brain counts of cryptococci were not lowered by miconazole; also, miconazole did not alter the effect of amphotericin B on reducing tissue counts. In vitro studies confirmed that the strain of Cryptococcus neoformans was quite susceptible to both miconazole and amphotericin B. However, miconazole had a delayed onset of antifungal activity. This was apparent even at miconazole levels 20 times greater than the minimum inhibitory concentration. Also, the antifungal activity of miconazole was markedly inhibited by serum. Delayed antifungal activity and serum inhibition may limit the in vivo effectiveness of miconazole in murine cryptococcosis.