4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies.

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.

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies.

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.

Synthesis, Characterization and Cholinesterase Inhibition Studies of New Arylidene Aminothiazolylethanone Derivatives.

BACKGROUND: Alzheimer's disease is caused by the destruction or loss of cholinergic cells that produce or use ACh in the brain, thereby reducing the availability of enzyme to other cells. The major treatment strategy for AD is to decrease the level of cholinesterase in the brain. OBJECTIVE: The aim of this study was to describe the effect of novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) as cholinesterase inhibitors (CEIs). METHOD: A novel series of thiazole derivatives i.e. arylidene aminothiazolylethanones (3a-h) was synthesized by treating 3-chloropentane-2,4-dione (1) with urea followed by reaction with suitably substituted benzaldehydes. Structural confirmation of all the synthesized compounds was carried out by spectroscopic techniques (FTIR, 1H and 13CNMR) and elemental analysis. Furthermore, these derivatives were subjected to biological evaluation as potential inhibitors of cholinesterases i.e. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). RESULTS: In all synthesized compounds except two compounds i.e. 3a and 3f, all compounds were identified as selective inhibitors of AChE. Compound 3a exhibited potent inhibitory values against AChE (IC50± SEM = 1.78±0.11 µM), exhibiting ≈7 times greater selectivity for AChE over BChE. Kinetics studies were performed to find out the mechanism of inhibition against respective enzyme. In addition, molecular docking studies of most potent inhibitors were also carried out to determine the binding interactions with AChE and BChE, respectively. CONCLUSION: In this study, novel thiazole derivatives i.e. arylidene aminothiazolylethanones were successfully synthesized, characterized and further screened for threir potential as cholinesterase inhibitors. All compounds were found as potent selective inhibitors of AChE except two compounds which exhibited dual inhibitory activities but both of these compounds were highly selective toward AChE as compared to BChE.