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Novel Phenylurea-Pyridinium Derivatives As Potent Urease Inhibitors: Synthesis, in Vitro, and in Silico Studies Publisher



Sadatebrahimi SE1 ; Bigdelou A1 ; Sooreshjani RH2 ; Montazer MN1 ; Zomorodian K3 ; Irajie C4 ; Yahyameymandi A1 ; Biglar M7 ; Larijani B2 ; Amanlou M7 ; Iraji A5, 6 ; Mahdavi M2
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Medical Mycology and Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
  4. 4. Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5. Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  6. 6. Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran
  7. 7. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Molecular Structure Published:2022


Abstract

Urease is known as a virulence factor of some pathogen in the living organism. In this study, a novel series of phenylurea conjugated to different alkyl pyridinium were designed, synthesized, and evaluated as urease inhibitors. The results of in vitro urease inhibition revealed that all derivatives were more potent than standard inhibitors, hydroxyurea (IC50 = 100.0 ± 2.5 μM) and thiourea (IC50 = 23.00 ± 0.84 μM) with IC50 value in the range of 4.08 to 6.20 μM. Kinetic assay of the most potent derivative, 4f, demonstrated a mixed type of inhibition. Docking studies confirmed the complete fitting of the synthesized compounds into the urease active site. According to microbial assay, 4f demonstrated high potency and selectivity against C. neoformans compared to the other tested pathogens. 4f also exhibited IC50 values of 143.42 ± 1.9 and 250.08 ± 5.81 µg/ml to inhibit urease enzyme against C. neoformans and P.vulgaris in the ureolytic assay. Also, in silico drug-likeness study revealed the favorable pharmacokinetic properties of synthesized derivatives. The results underline the potential role of phenylurea-pyridinium hybrids against urease in drug discovery. © 2022 Elsevier B.V.
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