Discovery of new imidazole derivatives containing the 2,4-dienone motif with broad-spectrum antifungal and antibacterial activity.

Chunli Liu,Fei Mao,Yong Xu,Mingjie Xiang,Jian Li,Jin Zhu,Jinyan Liu,Bing Wei,Ce Shi

doi:10.3390/molecules191015653

Abstract

A compound containing an imidazole moiety and a 2,4-dienone motif with significant activity toward several fungi was discovered in a screen for new antifungal compounds. Then, a total of 26 derivatives of this compound were designed, synthesized and evaluated through in vitro and in vivo antifungal activity assays. Several compounds exhibited improved antifungal activities compared to the lead compound. Of the derivatives, compounds 31 and 42 exhibited strong, broad-spectrum inhibitory effects toward Candida spp. In particular, the two derivatives exhibited potent antifungal activities toward the fluconazole-resistant isolate C. albicans 64110, with both having MIC values of 8 µg/mL. In addition, they had significant inhibitory effects toward two Gram-positive bacteria, Staphylococcus aureus UA1758 (compound 31: MIC = 8 µg/mL; compound 42: MIC = 4 µg/mL) and Staphylococcus epidermidis UF843 (compound 31: MIC = 8 µg/mL; compound 42: MIC = 8 µg/mL). The results of an animal experiment indicated that both compounds could improve the survival rate of model mice infected with ATCC 90028 (fluconazole-susceptible isolate). More importantly, the two compounds exhibited notable in vivo effects toward the fluconazole-resistant C. albicans isolate, which is promising with regard to the clinical problem posed by fluconazole-resistant Candida species.

Highlights

Infections caused by bacteria and fungi lead to diseases and an enormous social burden as millions of people are infected by bacteria and fungi every year worldwide
The development of derivatives based on heterocyclic scaffolds is a fast emerging subject in medicinal chemistry
A great deal of azole-based antibacterial and antifungal agents have been extensively studied as drug candidates, and some of them have been used in the clinic, for instance itraconazole, fluconazole, posaconazole and voriconazole, which suggests the great development value of azole compounds [8]

Summary

Introduction

Infections caused by bacteria and fungi lead to diseases and an enormous social burden as millions of people are infected by bacteria and fungi every year worldwide. A large number of antimicrobial drugs have been listed, which play an important role in treating infections [1]. Growing antifungal resistance poses the threat that there will be no available drugs for the treatment of common infections in the future [3], so there is an urgent need for the discovery of new compounds with antibacterial and antifungal activities [4], especially those with mechanisms of action that are distinct from the well-known classes of antifungal agents [5,6,7]. A great deal of azole-based antibacterial and antifungal agents have been extensively studied as drug candidates, and some of them have been used in the clinic, for instance itraconazole, fluconazole, posaconazole and voriconazole, which suggests the great development value of azole compounds [8]. The reduced susceptibility of Cryptococcus neoformans to fluconazole has been reported in a number of sub-Saharan countries including Kenya, Uganda, Rwanda and South

Methods

Results

Conclusion