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Indoleamine 2,3-dioxygenase 1 (IDO1) is the enzyme catalyzing the oxidative metabolism of tryptophan, which accounts for cancer immunosuppression in tumor microenvironment. Several compounds targeting IDO1 have been reported and epacadostat shows strong inhibitory activity against IDO1, which is further studied in clinic trails. However, its pharmacokinetic profiles are not satisfactory. The half-life of epacadostat is 2.4 h in human and dosage is 50 mg BID in the phase III clinic trial. To overcome the shortcomings of epacadostat, structure-based drug design was performed to improve the pharmacokinetic profiles via changing the metabolic pathway of epacadostat and to enhance anti-tumor potency. A novel series of 1,2,5-oxadiazole-3-carboximidamide derivatives bearing cycle in the side chain were designed, synthesized, and biologically evaluated for their anti-tumor activity. Most of them exhibited potent activity against hIDO1 in enzymatic assays and in HEK293T cells over-expressing hIDO1. Among them, compound 23 , 25 and 26 showed significant inhibitory activity against hIDO1 (IC 50 = 108.7, 178.1 and 139.1 nM respectively) and in HEK293T cells expressing hIDO1 (cellular IC 50 = 19.88, 68.59 and 57.76 nM respectively). Moreover, compound 25 displayed improved PK property with longer half-life (t 1/2 = 3.81 h in CD-1 mice) and better oral bioavailability (F = 33.6%) compared with epacadostat. In addition, compound 25 showed similar potency to inhibit the growth of CT-26 syngeneic xenograft compared to epacadostat, making it justifiable for further investigation. Image 1 • Novel 1,2,5-oxadiazole-3-carboximidamide derivatives as IDO1 inhibitors were designed, synthesized, and evaluated. • The structure-activity relationship (SAR) of this novel series of 27 compounds was demonstrated. • Compound 23 , 25 and 26 demonstrated potent in vitro inhibitory activity against hIDO1 (IC 50 = 108.7, 178.1 and 139.1 nM respectively) and compound 25 showed improved PK profiles (t 1/2 = 3.81 h, F = 33.6%) compared with epacadostat. • Compound 25 exhibited the similar anti-tumor efficacy with epacadostat without inducing significant change in body weight compared to the control group. [ABSTRACT FROM AUTHOR]

[Display omitted] • Application of machine learning methods to DL–CS co–pyrolysis. • D10C90 inhibits CO 2 production, which has implications for carbon neutrality. • Gaseous functional groups during the pyrolysis were examined by TG–FTIR. • Estimation of activation energy by KAS, FWO, and Starink methods. • The stacked XGB–LGBM–MLP model preform best of all individual models. Co–pyrolysis characteristics and thermo–kinetics of de–alkalized lignin (DL) and coconut shell (CS) were investigated by using TG–FTIR and machine learning methods. The DL–CS samples mixed in different proportions were heated from ambient temperature to 1173.15 K at 10, 15, and 20 K·min−1. The gas functional groups in the pyrolysis process of the experimental samples were detected by TG–FTIR. The apparent activation energy (E) was estimated by Flynne–Walle–Ozawa (FWO), Kissinger–Akahira–Sunose (KAS), and Starink methods, and the R 2 values of these three methods are greater than 0.97032, which means that the activation energy solved by these methods is feasible. An BP–NN model of 9×3×1 architecture was employed to predict the residual weight of DL–CS co–pyrolysis. The experimental values were in good agreement with the predicted values by BP–NN model (RMSE = 0.8606, R 2 = 0.99888). A Stacked XGB–LGBM–MLP model was employed to improve the overall prediction performance of DL–CS co–pyrolysis, and this model succeeds to preform best (RMSE = 0.1888, R 2 = 0.99995) of all individual models from test set result parameters. Our research results contribute to the optimal operating conditions for energy utilization, pollution control, and thermochemical conversion of lignin waste industry. [ABSTRACT FROM AUTHOR]

• We demonstrated the Fe-PTC monolayer can serve as a trifunctional electrocatalyst. • Fe-PTC has high electrocatalytic activity for HER with overpotential is −0.23 V. • The p-band center as descriptor is used to reveal the origins of catalytic activity. • Fe-PTC is a potential electrocatalyst for both OER and ORR with low overpotentials. Integrating high efficiency hydrogen evolution reaction (HER), oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) in multifunctional electrocatalysts is attractive for the unitized regenerative fuel cells and overall water splitting technologies. We demonstrated from first-principles calculations the recently- synthesized two-dimensional (2D) metal-organic frameworks (MOFs), namely transition metal 1,2,3,4,5,6,7,8,9,10,11,12- perthiolated coronene (TM-PTC) have multifunctional electrocatalytic activity for HER, OER and ORR. In particular, Fe-PTC monolayer can serve as a trifunctional electrocatalyst for overall water splitting and rechargeable metal-air battery with low overpotentials comparable to those of the well-developed unifunctional electrocatalysts. The origins of the trifunctional electrocatalytic activity were also discussed. This work is expected to open an avenue for the design of highly-efficient multifunctional electrocatalysts. [ABSTRACT FROM AUTHOR]

In this work, aiming at finding a novel, potent, and selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor with good pharmacokinetic profiles for the treatment of diabetes, we focus on modifying the sugar moiety of SGLT2 inhibitors, which dominates the binding with glucose binding site of hSGLT, via removing the C-6 hydroxy group to adjust the physicochemical properties and target-recognition manners of SGLT2 inhibitors. In addition, tofogliflozin containing a special O -spiroketal C -arylglucoside scaffold, displayed good efficacy and bioavailability both in animals and in humans. Therefore, a series of 6-deoxy O -spiroketal C -arylglucosides as novel SGLT2 inhibitors were designed, synthesized, and evaluated in this work. The structure-activity relationship (SAR) research on this novel series and a comprehensive in vitro and in vivo biological evaluation afforded compound 39 with high in vitro hSGLT2 inhibitory activity (IC 50 = 4.5 nM), good pharmacokinetic profiles, and more remarkable efficacy in C57BL/6J mice and Sprague-Dawley rats than marketed drug tofogliflozin. Image 1 • Novel 6-deoxy O -spiroketal C -arylglucosides as SGLT2 inhibitors were designed, synthesized, and evaluated. • The structure-activity relationship (SAR) of this novel series of 31 compounds was demonstrated. • Compound 39 demonstrated higher potency of inhibiting hSGLT2 than dapagliflozin (IC 50 = 4.5 nM vs 8.3 nM). • Compound 39 displayed greater efficacy than tofogliflozin on urinary glucose excretion and oral glucose tolerance in mice. • The half-life of compound 39 in mice was longer than tofogliflozin after oral administration (5.95 h vs 2.57 h). [ABSTRACT FROM AUTHOR]