Structure-Activity Relationships and Anti-inflammatory Activities of N-Carbamothioylformamide Analogues as MIF Tautomerase Inhibitors.
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is an attractive therapeutic target for the treatment of inflammatory diseases. In our previous study, 3-[(biphenyl-4-ylcarbonyl)carbamothioyl]amino benzoic acid (compound 1) was discovered as a potent inhibitor of MIF by docking-based virtual screening and bioassays. Here, a series of analogues of compound 1 derived from similarity search and chemical synthesis were evaluated for their MIF tautomerase activities, and their structure-activity relationships were then analyzed. The most potent inhibitor (compound 5) with an IC50 of 370 nM strongly suppressed lipopolysaccharide (LPS)-induced production of TNF-α and IL-6 in a dose-dependent manner and significantly enhanced the survival rate of mice with LPS-induced endotoxic shock from 0 to 35% at 0.5 mg/kg and to 45% at 1 mg/kg, highlighting the therapeutic potential of the MIF tautomerase inhibition in inflammatory diseases.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Yu
Y
Zhang
College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.|Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology , Changzhou 213001, China.
Lei
L
Xu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Zhiqiang
Z
Zhang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Zhiyu
Z
Zhang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Longtai
L
Zheng
College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
Dan
D
Li
Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
Youyong
Y
Li
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Feng
F
Liu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 200031, China.
Kunqian
K
Yu
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.|College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.|Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University , Suzhou, Jiangsu 215123, China.
Tingjun
T
Hou
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
Xuechu
X
Zhen
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000737:chemistry; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005559:Formamides / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009569:Nitric Oxide / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D001559:Benzhydryl Compounds; D004791:Enzyme Inhibitors; D005559:Formamides; D008263:Macrophage Migration-Inhibitory Factors; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D019746:Intramolecular Oxidoreductases; C022346:phenylpyruvate tautomerase; C010129:diphenylmethane