ABSTRACT
BACKGROUND: Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems. OBJECTIVE: This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors. METHODS: Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined. RESULTS: It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation. CONCLUSIONS: Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.
Subject(s)
Aminocoumarins/chemical synthesis , Aminocoumarins/pharmacology , Canavalia/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Molecular Docking Simulation , Urease/antagonists & inhibitors , Aminocoumarins/chemistry , Aminocoumarins/metabolism , Animals , Artemia , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Protein Conformation , Urease/chemistry , Urease/metabolismABSTRACT
Cardiovascular diseases are among the most threatening problems being faced by twenty-first century humans. The core cause of these diseases is high cholesterol level. Simvastatin (1: Synvinolin) is a well-known cholesterol-lowering drug marketed under the trade name Zocor®, which significantly reduces the risk of cardiovascular diseases related to hypercholesterolemia and is effective in lowering the total plasma cholesterol, low-density and very low-density lipoprotein cholesterol. It also enhances the high-density lipoprotein cholesterol. This review article aims to provide an overview of several chemical and biological methods utilized for the production of simvastatin in high yields and purity. Many robust and scalable methods have been described using lovastatin (2: Mevinolin) as a starting material, produced by the fungal strain of Aspergelius terreus. Enzymatic synthesis of simvastatin is also highlighted in this review. In addition, detailed experimental conditions, as well as the compatibility for industrial-scale preparations of simvastatin are also discussed.
