Design, synthesis and antifungal activities of novel triazole derivatives with selenium-containing hydrophobic side chains.

In this work, a series of novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). All compounds were characterized by HRMS, 1H NMR and 13C NMR. Then, their antifungal activities against eight human pathogenic fungi were evaluated in vitro by testing the minimal inhibitory concentrations. The results showed that nearly all tested compounds were found to be more potent against all tested fungal strains than control drug fluconazole. Further mechanism study demonstrated that the target compounds had fungal CYP51 inhibitory activity. Meanwhile, representative compounds revealed low cytotoxic effects toward mammalian cell lines. In addition, the docking results showed that the target compounds bound to Candida albicans CYP51 in a better pattern than fluconazole, especially in the narrow hydrophobic cleft. Overall, the novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains can be further developed for the potential treatment of invasive fungal infections.

Discovery of novel selenium-containing azole derivatives as antifungal agents by exploiting the hydrophobic cleft of CYP51.

Herein, we report the design, synthesis and evaluation of a novel series of diselenide and selenide derivatives as potent antifungal agents by exploiting the hydrophobic cleft of CYP51. Among all synthesized compounds, the most potent compound B01 with low cytotoxic and hemolysis effect exhibited excellent activity against C.alb., C.gla., C.par. and C.kru., as well as selected fluconazole-resistant strains. Moreover, compound B01 could reduce the biofilm formation of the FCZ-resistant C.alb. Subsequently, metabolic stability assays using liver microsomes demonstrated that compound B01 showed good profiles of metabolic stability. With superior pharmacological profile, compound B01 was advanced into in vivo bioactivity evaluation. In a murine model of systemic C.alb. infection, compound B01 significantly reduced fungal load of kidneys. Furthermore, compound B01 revealed relatively low acute toxicity and subacute toxicity in mice. In addition, docking study performed into C.alb. CYP51, showed the binding mode between C.alb. CYP51 and compound B01. Collectively, diselenides compound B01 can be further developed for the potential treatment of invasive fungal infections.

Whole-genome resequencing of wild and cultivated cannabis reveals the genetic structure and adaptive selection of important traits.

BACKGROUND: Cannabis is an important industrial crop species whose fibre, seeds, flowers and leaves are widely used by humans. The study of cannabinoids extracted from plants has been popular research topic in recent years. China is one of the origins of cannabis and one of the few countries with wild cannabis plants. However, the genetic structure of Chinese cannabis and the degree of adaptive selection remain unclear. RESULTS: The main morphological characteristics of wild cannabis in China were assessed. Based on whole-genome resequencing SNPs, Chinese cannabis could be divided into five groups in terms of geographical source and ecotype: wild accessions growing in the northwestern region; wild accessions growing in the northeastern region; cultivated accessions grown for fibre in the northeastern region; cultivated accessions grown for seed in northwestern region, and cultivated accessions in southwestern region. We further identified genes related to flowering time, seed germination, seed size, embryogenesis, growth, and stress responses selected during the process of cannabis domestication. The expression of flowering-related genes under long-day (LD) and short-day (SD) conditions showed that Chinese cultivated cannabis is adapted to different photoperiods through the regulation of Flowering locus T-like (FT-like) expression. CONCLUSION: This study clarifies the genetic structure of Chinese cannabis and offers valuable genomic resources for cannabis breeding.

Discovery of novel aminosaccharide-based sulfonamide derivatives as potential carbonic anhydrase II inhibitors.

In this paper, a new class of novel sulfonamides incorporating aminosaccharide tails were designed and synthesized based on the sugar-tail approach. Then, all the novel compounds were evaluated for their inhibitory activities against three carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes (hCA I, hCA II and hCA IX). Interestingly, effective inhibition of these three CA isoforms were observed, especially the glaucoma associated isoform hCA II. It is worth noting that these glycoconjugated sulfonamide derivatives also showed better CA inhibitory effects compared to the initial segment carzenide. Among them, compound 8d was the most effective inhibitor with IC50 of 60 nM against hCA II. Subsequent physicochemical properties studies showed that all compounds have good water solubility and neutral pH values in solutions. And these important physicochemical properties make target compounds acquire obvious advantages in the preparation of topical and nonirritating antiglaucoma drugs. Moreover, the target compounds showed lower corneal cytotoxicity than acetazolamide (AAZ) and good metabolic stability in vitro. In addition, molecular docking studies confirmed the interactions between aminosaccharide fragment and hydrophilic subpocket of hCA II active site were crucial for the enhanced CA inhibitory activity. Taken together, these results suggested 8d would be a promising lead compound for the development of topical antiglaucoma CAIs.

Discovery of 1,2,3-selenadiazole analogues as antifungal agents using a scaffold hopping approach.

With the increasing incidence of antifungal resistance, new antifungal agents having novel scaffolds hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. In this study, we reported the design, synthesis, and pharmacological evaluation of novel 1,2,3-selenadiazole analogues by scaffold hopping strategy. Preliminary results of antifungal activity demonstrated that the new class of compounds showed broad-spectrum fungistatic and fungicidal activity. Most importantly, these newly synthesized compounds can eliminate these azole-resistant fungi and inhibit the formation of C. albicans biofilm. In particular, compound S07 showed promising antifungal activity against five azole-resistant strains with MIC values ranging from 4 to 32 µg/mL. Then, further target identification and mechanistic studies indicated that representative compound S07 exert its inhibitory activity by inhibiting fungal lanosterol 14α-demethylase enzyme (CYP51). Interestingly, representative compounds showed low cytotoxicity on mammalian cell lines. In addition, the molecular docking studies elucidated the binding modes of these compounds toward CYP51. Altogether, these results suggest that compound S07 with novel skeleton is a promising CYP51 inhibitor for treatment of fungal infections.

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.

Design, synthesis, and biological evaluation of novel miconazole analogues containing selenium as potent antifungal agents.

Herein, based on the theory of bioisosterism, a series of novel miconazole analogues containing selenium were designed, synthesized and their inhibitory effects on thirteen strains of pathogenic fungi were evaluated. It is especially encouraging that all the novel target compounds displayed significant antifungal activities against all tested strains. Furthermore, all the target compounds showed excellent inhibitory effects on fluconazole-resistant fungi. Subsequently, preliminary mechanistic studies indicated that the representative compound A03 had a strong inhibitory effect on C.alb. CYP51. Moreover, the target compounds could prevent the formation of fungi biofilms. Further hemolysis test verified that potential compounds had higher safety than miconazole. In addition, molecular docking study provided the interaction modes between the target compounds and C.alb. CYP51. These results strongly suggested that some target compounds are promising as novel antifungal drugs.