ABSTRACT
With the aim of discovering novel IDO1 inhibitors, a combined similarity search and molecular docking approach was employed to the discovery of 32 hit compounds. Testing the screened hit compounds has led to several novel submicromolar inhibitors. Especially for compounds LVS-019 with cyanopyridine scaffold, showed good IDO1 inhibitory activity. To discover more compounds with similar structures to LVS-019, a shape-based model was then generated on the basis of it and the second-round virtual screening was carried out leading to 23 derivatives. Molecular docking studies suggested a possible binding mode of LVS-019, which provides a good starting point for the development of cyanopyridine scaffold compounds as potent IDO1 inhibitor. To improve potency of these hits, we further designed and synthesised another 14 derivatives of LVS-019. Among these compounds, LBJ-10 showed improved potency compared to the hits and displayed comparable potency to the control GDC-0919 analogue. LBJ-10 can serve as ideal leads for further modifications as IDO1 inhibitors for cancer treatment.
Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Pyridines/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Molecular Docking Simulation , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
An efficient reaction utilizing propargyl carbonates through Claisen rearrangement to synthesize furanonaphthoquinones is described. The remarkable transformation exhibits excellent functional group tolerance, affording the target furanonaphthoquinones in moderate to good yields (41-85%) under mild reaction conditions. Scaled-up preparation of the model product can make this reaction a method of choice for synthesis of furanonaphthoquinone derivatives. The resulting furanonaphthoquinones were evaluated as potential indoleamine 2,3-dioxygenase inhibitors in vitro.
Subject(s)
Carbonates/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Naphthoquinones/chemistry , Palladium/chemistry , Quinones/chemistry , Quinones/pharmacology , Catalysis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , HeLa Cells , Humans , StereoisomerismABSTRACT
The wide presence of antibiotics in the environment has raised concerns about their potential impact on ecological and human health. This study was conducted to evaluate the degradation of antibiotics (chlortetracycline (CTC) and oxytetracycline (OTC)) in microbial fuel cells (MFCs) and the change of toxicity. The degradation rates of 60 mg L-1 CTC and OTC in the MFCs were 74.2% and 78%, respectively, within 7 days. The degradation ability of the two antibiotics followed the order of OTC > CTC. Toxicity test results of the zebrafish illustrated the toxicity of OTC and CTC was largely eliminated by MFC treatment. Furthermore, possible degradation pathways of CTC and OTC were speculated using LC-MS analysis. High-throughput sequencing analysis indicated that Petrimonas, Azospirillum, Dokdonella, Burkholderia and Stenotrophomonas were the predominant genera in the MFC anode biofilm. Therefore, this work is of great significance for future studies on the treatment of antibiotics in wastewater by MFCs.
