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Invasive fungal infections pose a serious threat to public health and are associated with high mortality and incidence rates. The development of novel antifungal agents is urgently needed. Based on hit-to-lead optimization, a series of 2,4,6-trisubstituted triazine hydrazone compounds were designed, synthesized, and biological evaluation was performed, leading to the identification of compound 28with excellent in vitrosynergy (FICI range: 0.094–0.38) and improved monotherapy potency against fluconazole-resistant Candida albicansand Candida auris(MIC range: 1.0–16.0 μg/mL). Moreover, 28exhibited broad-spectrum antifungal activity against multiple pathogenic strains. Furthermore, 28could inhibit hyphal and biofilm formation, which may be related to its ability to disrupt the fungal cell wall. Additionally, 28significantly reduced the CFU in a mouse model of disseminated infection with candidiasis at a dose of 10 mg/kg. Overall, the triazine-based hydrazone compound 28with low cytotoxicity, hemolysis, and favorable ADME/T characteristics represents a promising lead to further investigation.

Thirty-one novel albaconazole derivatives were designed and synthesized based on our previous work. All compounds exhibited potent in vitroantifungal activities against seven pathogenic fungi. Among them, tetrazole compound D2was the most potent antifungal with MIC values of <0.008, <0.008, and 2 μg/mL against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus, respectively, the three most common and critical priority pathogenic fungi. In addition, compound D2also exhibited potent activity against fluconazole-resistant C. aurisisolates. Notably, compound D2showed a lower inhibitory activity in vitroagainst human CYP450 enzymes as well as a lower inhibitory effect on the hERG K+channel, indicating a low risk of drug–drug interactions and QT prolongation. Moreover, with improved pharmacokinetic profiles, compound D2showed better in vivoefficacy than albaconazole at reducing fungal burden and extending the survival of C. albicans-infected mice. Taken together, compound D2will be further investigated as a promising candidate.

ABSTRACTBackground: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest.Design:We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1mediumand PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed.Results:Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positiveCTCs, and 60% (21/35) had at least one PD-L1highCTCs. The disease control (DC) rate in PD-L1highpatients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1highCTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postiveCTC and PD-L1highCTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1highCTCs at baseline had predicative significance for progression free survival (PFS).Conclusions:We revealed that the abundance of PD-L1highCTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time.