Novel (thio)barbituric-phenoxy- N -phenylacetamide derivatives as potent urease inhibitors: synthesis, in vitro urease i
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ORIGINAL RESEARCH
Novel (thio)barbituric-phenoxy-N-phenylacetamide derivatives as potent urease inhibitors: synthesis, in vitro urease inhibition, and in silico evaluations Saeb Sedaghati 1 & Homa Azizian 2 & Mohammad Nazari Montazer 1 & Maryam Mohammadi-Khanaposhtani 3 & Mehdi Asadi 1 & Fatemeh Moradkhani 1 & Mehdi Shafiee Ardestani 4 & Mohammad Sadegh Asgari 5 & Azadeh YahyaMeymandi 6 & Mahmood Biglar 7 & Bagher Larijani 7 & Seyed Esmaeil Sadat-Ebrahimi 1 & Alireza Foroumadi 1 & Massoud Amanlou 1 & Mohammad Mahdavi 7 Received: 2 June 2020 / Accepted: 11 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract A novel series of (thio)barbituric-phenoxy-N-phenylacetamide derivatives 7a-l was synthesized and evaluated against Helicobacter pylori urease. The latter assay revealed that all the synthesized compounds 7a-l (IC50 = 0.69 ± 0.33–2.47 ± 0.23 μM) were significantly more potent than two used standard inhibitors, thiourea (IC50 = 23 ± 0.73 μM) and hydroxyurea (IC50 = 100 ± 1.7 μM). Docking study of the synthesized compounds demonstrated that these compounds as well fitted in the urease active site. Moreover, molecular dynamic study of the most potent compound 7d showed that this compound created important interactions with the active site flap residues, Cys592 and His593. Furthermore, in silico pharmacokinetic study predicted that all the synthesized compounds are drug-like. Keywords Urease . Synthesis . Barbituric acid . Docking . In silico . N-phenylacetamide
Introduction Urease (EC 3.5.1.5) is a metalloenzyme of amidohydrolase superfamily that catalyzes conversion of urea to ammonia and carbon dioxide and therefore plays pivotal role in nitrogen cycle [1]. In agriculture, the urea performance as efficient soil fertilizer is restricted due to environmental concerns and corps damage which is attributed to urease activity [2]. In addition,
urease has been discovered as the key virulence factor of many microorganisms such as Helicobacter pylori (H. pylori) [3]. Indeed, H. pylori infection leads to peptic and duodenal ulcer that could further result to gastric cancer that is the second cause of death in worldwide [4]. One of the most important ways to stop H. pylori activity is urease inhibitors [5]. On the other hand, there are evidences that showed microbial ureases are involved in the pathogenesis of diseases such as
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-020-01617-6) contains supplementary material, which is available to authorized users. * Mahmood Biglar [email protected]
3
Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
* Mohammad Mahdavi [email protected]
4
Department of Radiopharmacy and Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
5
School of Chemistry, College of Science, University of Tehran, Tehran, Iran
6
Department of Chemistry, Faculty of Science, University of Bi
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