During the past years, a tremendous growth in the incidence of systemic fungal infections has become a significant cause of morbidity and mortality in patients with AIDS and cancer. Although the triazole class of drugs has become the most widely used antifungal agents, narrow spectrum and serious cross-drug resistance have limited their roles. Above all, the need for the novel antifungal agents which have broad spectrum, good water solubility and high activity against azole-resistant strains has become more pressing. Therefore, the urge for novel antifungal agents which have broad spectrum, good water solubility and high activity against azole-resistant strains has shown a great significance.

Taken antifungal spectrum, drug-resistant characteristics, water-soluble and metabolic properties into account, Dr. YANG Yushe’s group of Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, designed and synthesized series of novel azoles with a five-membered heterocyclic ring (B ring) fused to the piperazine or piperidine (A ring) as side chains by using several structural optimization strategies, such as bioisosterism, transformation of molecular skeleton and pharmacophore. Among these derivatives with independent intellectual property rights, compound YC-071 was identified as the candidate compound.

Compound YC-071 exhibited excellent activity against common pathogenic strains, most importantly, it also showed remarkable activity against several azole-resistant strains, which was superior to the potent antifungal agent, voriconazole. Mice infected with C.alb. SC5314 and C.alb. 103 (fluconazole-resistant strain) and administered with YC-071 displayed significantly improved survival rates. Apart from that, it also showed that compound YC-071 with excellent pharmacokinetic properties protected mice infected in a dose-dependent fashion.

This research work was performed by Dr. Cao Xufeng and joint postgraduate Sun Zhaoshuan from Dr. Hu Wenhao’s group of East China Normal University. This work has been published on Journal of Medicinal Chemistry (2014, 57, 3687-3706).

Candidate drug YC-071 has been supported by the Key New Drug Creation and Manufacturing Program of the “Twelfth Five-year Plan” of China (No. 2014ZX09101004-003).

Linker: http://pubs.acs.org/doi/abs/10.1021/jm4016284

Figure 1. Previous selected compounds and new structures.(Image by SIMM)