Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors

Abstract

BackgroundDiscovery of potent inhibitors of urease (jack bean) enzyme is the first step in the development of drugs against diseases caused by ureolytic enzyme.ResultsThirty-two derivatives of barbituric acid as zwitterionic adducts of diethyl ammonium salts were synthesized. All synthesized compounds (4a–z and 5a–s) were screened for their in vitro inhibition potential against urease enzyme (jack bean urease). The compounds 4i (IC50 = 17.6 ± 0.23 µM) and 5l (IC50 = 17.2 ± 0.44 µM) were found to be the most active members of the series, and showed several fold more urease inhibition activity than the standard compound thiourea (IC50 = 21.2 ± 1.3 µM). Whereas, compounds 4a–b, 4d–e, 4g–h, 4j–4r, 4x, 4z, 5b, 5e, 5k, 5n–5q having IC50 values in the range of 22.7 ± 0.20 µM–43.8 ± 0.33 µM, were also found as potent urease inhibitors. Furthermore, Molecular Dynamics simulation and molecular docking studies were carried out to analyze the binding mode of barbituric acid derivatives using MOE. During MD simulation enol form is found to be more stable over its keto form due to their coordination with catalytic Nickel ion of Urease. Additionally, structural–activity relationship using automated docking method was applied where the compounds with high biological activity are deeply buried within the binding pocket of urease. As multiple hydrophilic crucial interactions with Ala169, KCX219, Asp362 and Ala366 stabilize the compound within the binding site, thus contributing greater activity.ConclusionsThis research study is useful for the discovery of economically, efficient viable new drug against infectious diseases.Graphical abstract:STD. Thiourea (IC50 = 21.2 ± 1.3 µM)Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-015-0140-1) contains supplementary material, which is available to authorized users.

Synthesis, X-Ray Crystal Structures, Biological Evaluation, and Molecular Docking Studies of a Series of Barbiturate Derivatives

“…Chemistry. We have been focusing on the development of highly expedient methods for the synthesis of diverse heterocyclic compounds of biological importance via onepot multicomponent reactions (MCRs) and avoiding organic solvents in organic synthesis [17,19,20]. This had led to the development of several efficient, environmentally benign, clean, and economical process technology (Green Chemistry Concepts).…”

“…This had led to the development of several efficient, environmentally benign, clean, and economical process technology (Green Chemistry Concepts). In current reaction strategy, equimolar amounts of barbituric acid (1) and dimedone (2) with aldehyde (3) in the presence of aqueous diethylamine medium at RT yielded salts of PYT adducts 4a-4y and 5a-5m were obtained in quantitative yields by simple filtration [17][18][19][20].…”

“…The focus in recent years is on the development of resource-efficient, environmentally benign, and sustainable chemistry practices. In continuation of our work in this field, we describe here the synthesis of a series of previously reported [17,19,20] and new PYT adducts. These compounds were evaluated for their antioxidant activity by using DDPH scavenging assay, as well as for in vitro enzyme inhibition activities against alpha-glucosidase, thymidine phosphorylase, and -glucuronidase enzymes.…”

3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model

“…In this regard, the 3D-QSAR technique is extensively utilized to develop and predict the bio-activities of novel compounds. Comparative Molecular Similarity Indices Analysis (CoMSIA) and Comparative Molecular Field Analysis (CoMFA) are versatile and powerful 3D-QSAR techniques to build a model for a specified compounds set in drug design and other linked applications [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

5-[(3-Fluorophenyl)(2-hydroxy-6-oxocyclohex-1-en-1-yl)methyl]-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

“…The barbituric acid skeleton represents an important structural motif that is embodied in a number of pharmaceutical agents with activities including anti-osteoporosis [1][2][3], anticonvulsant [4,5], urease inhibition [6,7], sedation, anesthesia [8,9], hypnosis [10], anti-oxidant [11], radio-sensitization, tyrosinase or alpha-glucosidase inhibition [12,13], anti-bacterial [14], anti-fungal [14], anti-cancer [14], and anxiolytic effects [3]. Many of these representatives are in clinical use as hypnotic and anti-inflammatory drugs; for example, sodium pentothal, phenobarbital, veronal, seconal, and bucolome [8,9].…”