Human lactate dehydrogenase A (LDHA) is an NADH-dependent oxidoreductase that catalyzes the conversion of pyruvate to lactate, playing a crucial role in the aerobic glycolysis of tumor cells. Additionally, LDHA is responsible for catalyzing the conversion of glyoxylate to oxalate in the liver, excessive accumulation of which leads to hyperoxaluria. Representative LDHA inhibitors reported to date include GNE-140, NCATS-SM1441, and CHK-336. In this study, NCATS-SM1441 was used as the lead compound. Based on the analysis of its cocrystal binding mode with LDH, the key carboxythiazole and aromatic pharmacophores were retained, while the original substituted pyrazole linker was replaced with urea linker moieties to simplify the structure. As a result, nine urea derivatives were designed and synthesized. Subsequently, on the basis of structure-activity relationship and molecular docking studies, nine target triazole compounds were further designed. Ultimately, triazole compound 25 was found to exhibit the most potent LDHA inhibitory activity (IC50 = 1.59 μmol/L) in vitro. Molecular dynamics simulations were employed to analyze the interactions between compound 25 and key amino acid residues. Finally, the prediction of physicochemical properties and the evaluation of cell viability were performed for compound 25. The study provides an experimental basis for future development of novel LDHA inhibitors with improved drugability.

Objective:To analysis clinical curative effect of laparoscopic radical prostatectomy bladder cancer and influence on serum levels of ferritin (SF),soluble interleukin-2 receptor (SIL-2 R) and rumor specific growth factor (TSGF).Methods:98 cases of bladder cancer who were treated in our hospital from August 2012 to February 2016 were selected and randomly divided into the control group 0=49) and the research group (n=49).The patients in the control group were treated with open radical radical cystectomy,while the patients in the research group were treated with laparoscopic radical cystectomy.Then the operation time,intraoperative blood loss,anal exhaust time,hospitalization,the lymph node cleaning,the serum levels of SF,SIL-2R,TSGF,white blood cells and cortisol,the complications and recurrence rate in the two groups were observed and compared.Results:The operation time of research group was longer than that of the control group,while the intraoperative blood loss,the hospitalization and the anal exhaust time were less than those of the control group,and the differences were statistically significant (P＜0.05).There was no statistically significant difference about the numbers of the lymph node and the recurrence rate between two groups (P＜0.05).After treatment,the serum levels of SF,SIL-2R and TSGF in the two groups decreased,while there was no statistically significant difference between the two groups (P＞0.05);After treatment,the white blood cell count and cortisol rise in the two groups increased,while the research group was lower than that of the control group (P＜0.05).Conclusion:LRC and ORC clinical efficacy similar,both of which can reduce the serum levels of SF,SIL-2R and TSGF of patients with laparoscopic radical prostatectomy bladder cancer.