Syntheses of 4,6-dihydroxypyrimidine diones, their urease inhibition, in vitro, in silico, and kinetic studies

Muhammad, Munira Taj; Khan, Khalid Mohammed; Arshia,; Khan, Ajmal; Arshad, Fiza; Fatima, Bibi; Choudhary, M. Iqbal; Syed, Naima

doi:10.1016/j.bioorg.2017.08.018

Cited by 12 publications

(8 citation statements)

References 18 publications

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“…Moreover, most of the urease inhibitors have a moiety (e.g., OH, thio/urea) in their scaffold to bind coordinately to Ni 2+ ions situated in the active site. [ 11,18–20 ] Thus, titled derivatives including diverse substitutions such as COOH, OH, ester, and carbonyl groups were designed based on the previous studies' results to bind coordinately to Ni 2+ ions and flap region amino acids.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Ahangarzadeh

Shakour

Rezvanpoor

et al. 2022

Archiv der Pharmazie

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The urease enzyme, a metalloenzyme having Ni 2+ ions, is recognized in some bacteria, fungi, and plants. Particularly, it is vital to the progress of infections induced by pathogenic microbes, such as Proteus mirabilis and Helicobacter pylori. Herein, we reported the synthesis of a series of tetrahydropyrimidine derivatives and evaluated their antiurease activity. Finally, quantitative and qualitative analyses of the derivatives were performed via in silico studies. Urease inhibitory activity was determined as the reaction of H. pylori urease with different concentrations of compounds, and thiourea was used as a standard compound. Docking and dynamics methodologies were applied to study the interactions of the best compounds with the amino acids in the active site. All compounds showed good to excellent antiurease activity. The potent compounds were not cytotoxic against the HUVEC normal cell line. Based on the docking study, compound 4e with the highest urease inhibitory activity (IC 50 = 6.81 ± 1.42 µM) showed chelates with both Ni 2+ ions of the urease active site. Further, compound 4f displayed a very good inhibitory activity (IC 50 = 8.45 ± 1.64 μM) in comparison to thiourea (IC 50 = 22.03 ± 1.24 μM). The molecular docking and dynamics simulation results were correlated with the in vitro assay results. Moreover, the derivatives 4a-n followed Lipinski's rule-of-five and had drug-likeness properties.

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Section: Resultsmentioning

confidence: 99%

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Ahangarzadeh

Shakour

Rezvanpoor

et al. 2022

Archiv der Pharmazie

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“…Compound 6238-0047 could interact with Cys318 to interfere with the normal function of the active site flap. All these binding modes showed that compound 6238-0047 could not only bind and interact with residues in the active site pocket but also with the flap outside the active side and these binding behaviors often result in a mixed type inhibitor in the previous report [ 28 , 29 , 30 ] and the kinetic study of compound 6238-0047 confirmed that it was a mixed type inhibitor.…”

Section: Discussionmentioning

confidence: 55%

A Novel Urease Inhibitor of Ruminal Microbiota Screened through Molecular Docking

Zhang

et al. 2020

IJMS

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Inhibition of the urease activity of ruminal microbiota is not only beneficial for increasing dietary and endogenic urea-N utilization efficiency in ruminants but also might be applicable for the preservation of nitrogen fertilizer in soil and treatment of gastrointestinal and urinary tract infections caused by ureolytic bacteria. To discover urease inhibitors to efficiently target ruminal microbiota, the identified ruminal microbial metagenomic urease gene was used to construct a homology model to virtually screen urease inhibitors from the ChemDiv database by molecular docking. The GMQE and QMEAN values of the homology model were 0.85 and −0.37, respectively, indicating a good model quality. The inhibition effect of the screened urease inhibitor for ruminal urea degradation was assessed by ruminal microbial fermentation in vitro. The toxic effect of the candidate inhibitor was performed using gut Caco-2 cells in vitro. The results showed that compound 3-[1-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-1H-pyrrol-2-yl] propanoic acid (ChemDiv_ID: 6238-0047, IC50 = 65.86 μM) was found to be the most effective urease inhibitor among the candidate compounds. Compound 6238-0047 significantly lowered the amount of urea degradation and ammonia production in ruminal microbial fermentation. The 24 h degradation rate of compound 6238-0047 in ruminal microbial fermentation was 3.32%–16.00%. In addition, compound 6238-0047 (10–100 μM) had no significant adverse effect on the cell viability of Caco-2 cells. Molecular docking showed that compound 6238-0047 could interact with Asp359 in the active site and Cys318 in the flap region by the hydrogen bond and Pi-Alkyl interaction, respectively. Compound 6238-0047 could be used as a novel inhibitor for decreasing the urease activity of ruminal microbiota.

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“…Barbiturates and thiobarbiturates have also been extensively studied due to their urea-bearing structure. However, barbituric and thiobarbituric acid analogues are also typically associated with moderate-to-low activity. − These molecules were aggregated in cluster 4 (Figure , M.5. ), which showed high median intracluster similarity (0.46) despite the relatively large size ( N = 130), and low percentage of actives (34.6%).…”

Section: Resultsmentioning

confidence: 99%

Exploring the Chemical Space of Urease Inhibitors to Extract Meaningful Trends and Drivers of Activity

Aniceto

Bonifácio

Guedes

et al. 2022

J. Chem. Inf. Model.

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Blocking the catalytic activity of urease has been shown to have a key role in different diseases as well as in different agricultural applications. A vast array of molecules have been tested against ureases of different species, but the clinical translation of these compounds has been limited due to challenges of potency, chemical and metabolic stability as well as promiscuity against other proteins. The design and development of new compounds greatly benefit from insights from previously tested compounds; however, no large-scale studies surveying the urease inhibitors’ chemical space exist that can provide an overview of developed compounds to data. Therefore, given the increasing interest in developing new compounds for this target, we carried out a comprehensive analysis of the activity landscape published so far. To do so, we assembled and curated a data set of compounds tested against urease. To the best of our knowledge, this is the largest data set of urease inhibitors to date, composed of 3200 compounds of diverse structures. We characterized the data set in terms of chemical space coverage, molecular scaffolds, distribution with respect to physicochemical properties, as well as temporal trends of drug development. Through these analyses, we highlighted different substructures and functional groups responsible for distinct activity and inactivity against ureases. Furthermore, activity cliffs were assessed, and the chemical space of urease inhibitors was compared to DrugBank. Finally, we extracted meaningful patterns associated with activity using a decision tree algorithm. Overall, this study provides a critical overview of urease inhibitor research carried out in the last few decades and enabled finding underlying SAR patterns such as under-reported chemical functional groups that contribute to the overall activity. With this work, we propose different rules and practical implications that can guide the design or selection of novel compounds to be screened as well as lead optimization.

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Syntheses of 4,6-dihydroxypyrimidine diones, their urease inhibition, in vitro, in silico, and kinetic studies

Cited by 12 publications

References 18 publications

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

A Novel Urease Inhibitor of Ruminal Microbiota Screened through Molecular Docking

Exploring the Chemical Space of Urease Inhibitors to Extract Meaningful Trends and Drivers of Activity

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