Symmetrical Heterocyclic Cage Skeleton: Synthesis, Urease Inhibition Activity, Kinetic Mechanistic Insight, and Molecular Docking Analyses

Hanif, Muhammad; Kanwal, Fariha; Rafiq, Muhammad; Hassan, Mubashir; Mustaqeem, Muhammad; Seo, Sung‐Yum; Zhang, Yunlong; Lu, Changrui; Chen, Ting; Saleem, Muhammad

doi:10.3390/molecules24020312

Cited by 19 publications

(18 citation statements)

References 33 publications

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“…In the literature, it is reported that enzymes such as urease and HRP are involved in the metabolism of HU. , Therefore, in the present study, we evaluated the effects of rutin and gallic acid on urease and HRP activity (Figure and Figure ). Thiourea was found to have an IC 50 of 30 μM against urease activity, corroborating a previous study, which also reported similar IC 50 . Rutin and gallic acid demonstrated IC 50 values of 780 and 635 μM, respectively, toward inhibition of urease activity.…”

Section: Resultssupporting

confidence: 88%

Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches

et al. 2021

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Hydroxyurea (HU) is the first-ever approved drug by USFDA for sickle cell anemia (SCA). However, its treatment is associated with severe side effects like myelosuppression. Current studies are focused on the supplementation therapy for symptomatic management of SCA. In the present study, we aimed to explore rutin's and gallic acid's potential individually, for concomitant therapy with HU using pharmacokinetic and pharmacodynamic approaches since there is no such precedent till date. In vivo pharmacokinetic studies of HU in rats showed that rutin could be safely co-administered with HU, while gallic acid significantly raised the plasma concentration of HU. Both the phytochemicals did not have any marked inhibitory effect on urease but have considerable effects on horseradish peroxidase enzyme. The experimental phytoconstituents displayed a very low propensity to cause in vitro hemolysis. Gallic acid markedly enhanced the HU-induced decrease in lymphocyte proliferation. A substantial improvement by rutin or gallic acid was observed in HU-induced reduction of the main hematological parameters in rats. Combined treatment of HU with rutin and gallic acid reduced serum levels of both IL-6 and IL-17A. Overall, both rutin and gallic acid are found to have promising phytotherapy potential with HU. Further exploration needs to be done on both candidates for use as phytotherapeutics for SCA.

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Section: Resultssupporting

confidence: 88%

Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches

et al. 2021

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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: 56%

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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“…The Protein Data Bank (PDB) was used to retrieve the structure of the jack bean urease enzyme PDBID 4H9M [ 27 ]. The University of California, San Francisco (UCSF) Chimera 1.10.1 tool was used to save the crystal structure of the enzyme in its stable conformation [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Enzyme Inhibitory Kinetics and Molecular Docking Studies of Halo-Substituted Mixed Ester/Amide-Based Derivatives as Jack Bean Urease Inhibitors

Rashid

Rafique

Roshan

et al. 2020

BioMed Research International

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A series of halo-substituted mixed ester/amide-based analogues 4a-l have been prepared as jack bean urease inhibitor, which showed good to excellent inhibition of enzyme activity. The role of halo-substituted benzoyl moieties and alkyl substituted anilines in urease inhibitory kinetics was also investigated. The alkyl-substituted anilines 1a–b reacted with chloroacetyl chloride to afford intermediates 2a-b, which were then reacted with different halo-substituted benzoic acids 3a–f to prepare the title compounds 4a-l. The chemical structures of final products 4a-l were ascertained by FTIR, 1H NMR, 13C NMR, and mass spectra. The compound 4b showed remarkable activity with IC50 1.6 ± 0.2 nM, better than the standard thiourea having IC50 472.1 ± 135.1 nM. The 2-chloro-substituted phenyl ring on one side of compound 4b and 4-isopropyl-substituted benzene on the other side play an essential role in inhibition of urease activity. Lineweaver–Burk plots (kinetics study) indicated about 4b derivative as a mixed type of inhibitor. The virtual screening performed against urease enzyme (PDBID 4H9M) showed that compounds 4b and 4e have binding energies of −7.8 and −7.9 Kcal/mol, respectively. Based upon our results, it was found that derivative 4b is a highly potent urease inhibitor, better than the standard thiourea.

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Symmetrical Heterocyclic Cage Skeleton: Synthesis, Urease Inhibition Activity, Kinetic Mechanistic Insight, and Molecular Docking Analyses

Cited by 19 publications

References 33 publications

Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches

Effect of Concomitant Hydroxyurea Therapy with Rutin and Gallic Acid: Integration of Pharmacokinetic and Pharmacodynamic Approaches

A Novel Urease Inhibitor of Ruminal Microbiota Screened through Molecular Docking

Enzyme Inhibitory Kinetics and Molecular Docking Studies of Halo-Substituted Mixed Ester/Amide-Based Derivatives as Jack Bean Urease Inhibitors

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