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Synthesis and Identification of New N , N -Disubstituted Thiourea, and Thiazolidinone Scaffolds Based on Quinolone Moiety as Urease Inhibitor

ORCID
0000-0003-4332-6345
Affiliation
Organic and Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Menoufia 32958, Egypt
Elshaier, Yaseen A. M. M.;
ORCID
0000-0002-0314-3408
Affiliation
Department of Chemistry, Faculty of Science, Minia University, El-Minia 61519, Egypt
Aly, Ashraf A.;
Affiliation
Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, El-Minia 61519, Egypt
Abdel-Aziz, Mohamed;
Affiliation
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assuit 71524, Egypt
Fathy, Hazem M.;
Affiliation
Chemistry Department, Florida Institute of Technology, Melbourne, FL 32901, USA
Brown, Alan B.;
ORCID
0000-0003-4845-3191
Affiliation
Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany
Bräse, Stefan;
Affiliation
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assuit 71524, Egypt
Ramadan, Mohamed

Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N , N -disubstituted thioureas. Finally, on subjecting the N , N -disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N , N -disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure−activity relationship revealed that N -methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC 50 = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein−ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N , N -disubstituted thiourea.

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