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

European Journal of Medicinal Chemistry
Hang XuChun Guo

Abstract

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 prov...Continue Reading

References

Aug 21, 2012·Bioorganic & Medicinal Chemistry·Muthu K KathiravanSandeep Gadhwe
Sep 6, 2014·Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (GMS)·Isabela Bueno RossetiMaricilia Silva Costa
Apr 7, 2015·Expert Review of Anti-infective Therapy·David AllenJohn Perfect
Jun 30, 2015·Current Clinical Microbiology Reports·David S PerlinYanan Zhao
Jul 11, 2016·European Journal of Internal Medicine·Spinello AntinoriMario Corbellino
Jan 5, 2017·Journal of Medicinal Chemistry·Shanchao WuChunquan Sheng
May 10, 2017·Expert Review of Anti-infective Therapy·Matthew W McCarthy, Thomas J Walsh
Aug 18, 2017·Infection and Drug Resistance·Elizabeth L Berkow, Shawn R Lockhart
Sep 19, 2017·Infection and Drug Resistance·Nathan P Wiederhold
Jan 3, 2018·Journal of Medicinal Chemistry·Na LiuChunquan Sheng
Apr 13, 2018·Parasitology·Galina I LepeshevaMichael R Waterman

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