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4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies.
Med Chem. 2020; 16(2):229-243.MC

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.

Authors+Show Affiliations

Department of Chemistry, Quaid-i-Azam University, 45320, Islamabad, Pakistan.Department of Chemistry, Quaid-i-Azam University, 45320, Islamabad, Pakistan.Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.Department of Physiology, University of Sindh, Jamshoro, Pakistan.Department of Chemistry, Quaid-i-Azam University, 45320, Islamabad, Pakistan.Department of Chemistry, Quaid-i-Azam University, 45320, Islamabad, Pakistan.Department of Biology, College of Natural Sciences, Kongju National University, Gongju, Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31309895

Citation

Fattah, Tanzeela A., et al. "4-Aminocoumarin Based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies." Medicinal Chemistry (Shariqah (United Arab Emirates)), vol. 16, no. 2, 2020, pp. 229-243.
Fattah TA, Saeed A, Ashraf Z, et al. 4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies. Med Chem. 2020;16(2):229-243.
Fattah, T. A., Saeed, A., Ashraf, Z., Abbas, Q., Channar, P. A., Larik, F. A., & Hassan, M. (2020). 4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies. Medicinal Chemistry (Shariqah (United Arab Emirates)), 16(2), 229-243. https://doi.org/10.2174/1573406415666190715164834
Fattah TA, et al. 4-Aminocoumarin Based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies. Med Chem. 2020;16(2):229-243. PubMed PMID: 31309895.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies. AU - Fattah,Tanzeela A, AU - Saeed,Aamer, AU - Ashraf,Zaman, AU - Abbas,Qamar, AU - Channar,Pervaiz A, AU - Larik,Fayaz A, AU - Hassan,Mubashir, PY - 2018/06/29/received PY - 2019/04/05/revised PY - 2019/06/07/accepted PY - 2019/7/17/pubmed PY - 2020/9/15/medline PY - 2019/7/17/entrez KW - Ammonia KW - aroylthioureas KW - docking studies KW - enzyme inhibitory kinetics KW - synthesis KW - urease inhibitors. SP - 229 EP - 243 JF - Medicinal chemistry (Shariqah (United Arab Emirates)) JO - Med Chem VL - 16 IS - 2 N2 - 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. SN - 1875-6638 UR - https://www.unboundmedicine.com/medline/citation/31309895/4_Aminocoumarin_based_Aroylthioureas_as_Potential_Jack_Bean_Urease_Inhibitors L2 - http://www.eurekaselect.com/173493/article DB - PRIME DP - Unbound Medicine ER -