Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole
Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stag...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/5/580 |
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| author | Martin Juhás Andrea Bachtíková Daria Elżbieta Nawrot Paulína Hatoková Vinod Sukanth Kumar Pallabothula Adéla Diepoltová Ondřej Janďourek Pavel Bárta Klára Konečná Pavla Paterová Vít Šesták Jan Zitko |
| author_facet | Martin Juhás Andrea Bachtíková Daria Elżbieta Nawrot Paulína Hatoková Vinod Sukanth Kumar Pallabothula Adéla Diepoltová Ondřej Janďourek Pavel Bárta Klára Konečná Pavla Paterová Vít Šesták Jan Zitko |
| author_sort | Martin Juhás |
| collection | DOAJ |
| description | Antimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted <i>N</i>-oxazolyl- and <i>N</i>-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially <i>Mycobacterium tuberculosis</i> (best MIC<sub>H37Ra</sub> = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k’<sub>w</sub> and water solubility (log <i>S</i>) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial β-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations. |
| first_indexed | 2024-03-10T03:09:15Z |
| format | Article |
| id | doaj.art-272fa446ccac49b29f63ff1088d904e1 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:09:15Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-272fa446ccac49b29f63ff1088d904e12023-11-23T12:34:52ZengMDPI AGPharmaceuticals1424-82472022-05-0115558010.3390/ph15050580Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-AminooxazoleMartin Juhás0Andrea Bachtíková1Daria Elżbieta Nawrot2Paulína Hatoková3Vinod Sukanth Kumar Pallabothula4Adéla Diepoltová5Ondřej Janďourek6Pavel Bárta7Klára Konečná8Pavla Paterová9Vít Šesták10Jan Zitko11Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicDepartment of Clinical Microbiology, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech RepublicDepartment of Clinical Biochemistry and Diagnostics, Faculty of Medicine in Hradec Králové, University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech RepublicAntimicrobial drug resistance is currently one of the most critical health issues. Pathogens resistant to last-resort antibiotics are increasing, and very few effective antibacterial agents have been introduced in recent years. The promising drug candidates are often discontinued in the primary stages of the drug discovery pipeline due to their unspecific reactivity (PAINS), toxicity, insufficient stability, or low water solubility. In this work, we investigated a series of substituted <i>N</i>-oxazolyl- and <i>N</i>-thiazolylcarboxamides of various pyridinecarboxylic acids. Final compounds were tested against several microbial species. In general, oxazole-containing compounds showed high activity against mycobacteria, especially <i>Mycobacterium tuberculosis</i> (best MIC<sub>H37Ra</sub> = 3.13 µg/mL), including the multidrug-resistant strains. Promising activities against various bacterial and fungal strains were also observed. None of the compounds was significantly cytotoxic against the HepG2 cell line. Experimental measurement of lipophilicity parameter log k’<sub>w</sub> and water solubility (log <i>S</i>) confirmed significantly (typically two orders in logarithmic scale) increased hydrophilicity/water solubility of oxazole derivatives in comparison with their thiazole isosteres. Mycobacterial β-ketoacyl-acyl carrier protein synthase III (FabH) was suggested as a probable target by molecular docking and molecular dynamics simulations.https://www.mdpi.com/1424-8247/15/5/580aminooxazoleaminothiazoleantimycobacterial activitydockingmolecular dockingmolecular dynamics |
| spellingShingle | Martin Juhás Andrea Bachtíková Daria Elżbieta Nawrot Paulína Hatoková Vinod Sukanth Kumar Pallabothula Adéla Diepoltová Ondřej Janďourek Pavel Bárta Klára Konečná Pavla Paterová Vít Šesták Jan Zitko Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole Pharmaceuticals aminooxazole aminothiazole antimycobacterial activity docking molecular docking molecular dynamics |
| title | Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole |
| title_full | Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole |
| title_fullStr | Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole |
| title_full_unstemmed | Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole |
| title_short | Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole |
| title_sort | improving antimicrobial activity and physico chemical properties by isosteric replacement of 2 aminothiazole with 2 aminooxazole |
| topic | aminooxazole aminothiazole antimycobacterial activity docking molecular docking molecular dynamics |
| url | https://www.mdpi.com/1424-8247/15/5/580 |
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