Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase
Tuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of <i>N</i>-(1-hydroxy-1,3-dihydrobenzo[<i>c</...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2951 |
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| author | Petr Šlechta Adam Anthony Needle Ondřej Jand’ourek Pavla Paterová Klára Konečná Pavel Bárta Jiří Kuneš Vladimír Kubíček Martin Doležal Marta Kučerová-Chlupáčová |
| author_facet | Petr Šlechta Adam Anthony Needle Ondřej Jand’ourek Pavla Paterová Klára Konečná Pavel Bárta Jiří Kuneš Vladimír Kubíček Martin Doležal Marta Kučerová-Chlupáčová |
| author_sort | Petr Šlechta |
| collection | DOAJ |
| description | Tuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of <i>N</i>-(1-hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides 1–19 via the acylation of 6-aminobenzo[<i>c</i>][1,2]oxaborol-1(3<i>H</i>)-ol with various activated (hetero)arylcarboxylic acids. These novel compounds have been tested in vitro against a panel of clinically important fungi and bacteria, including mycobacteria. Some of the compounds inhibited the growth of mycobacteria in the range of micromolar concentrations and retained this activity also against multidrug-resistant clinical isolates. Half the maximal inhibitory concentrations against the HepG2 cell line indicated an acceptable toxicological profile. No growth inhibition of other bacteria and fungi demonstrated selectivity of the compounds against mycobacteria. The structure–activity relationships have been derived and supported with a molecular docking study, which confirmed a selectivity toward the potential target leucyl-tRNA synthetase without an impact on the human enzyme. The presented compounds can become important materials in antimycobacterial research. |
| first_indexed | 2024-03-11T09:39:47Z |
| format | Article |
| id | doaj.art-4fa4428dfe1442afbe0a7f273e8e7758 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:39:47Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4fa4428dfe1442afbe0a7f273e8e77582023-11-16T17:04:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01243295110.3390/ijms24032951Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA SynthetasePetr Šlechta0Adam Anthony Needle1Ondřej Jand’ourek2Pavla Paterová3Klára Konečná4Pavel Bárta5Jiří Kuneš6Vladimír Kubíček7Martin Doležal8Marta Kučerová-Chlupáčová9Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Clinical Microbiology, University Hospital, 500 05 Hradec Králové, Czech RepublicDepartment of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicDepartment of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech RepublicTuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of <i>N</i>-(1-hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides 1–19 via the acylation of 6-aminobenzo[<i>c</i>][1,2]oxaborol-1(3<i>H</i>)-ol with various activated (hetero)arylcarboxylic acids. These novel compounds have been tested in vitro against a panel of clinically important fungi and bacteria, including mycobacteria. Some of the compounds inhibited the growth of mycobacteria in the range of micromolar concentrations and retained this activity also against multidrug-resistant clinical isolates. Half the maximal inhibitory concentrations against the HepG2 cell line indicated an acceptable toxicological profile. No growth inhibition of other bacteria and fungi demonstrated selectivity of the compounds against mycobacteria. The structure–activity relationships have been derived and supported with a molecular docking study, which confirmed a selectivity toward the potential target leucyl-tRNA synthetase without an impact on the human enzyme. The presented compounds can become important materials in antimycobacterial research.https://www.mdpi.com/1422-0067/24/3/2951antimicrobialantimycobacterialbenzoxaborolecytotoxicitymolecular dockingmultidrug-resistant tuberculosis |
| spellingShingle | Petr Šlechta Adam Anthony Needle Ondřej Jand’ourek Pavla Paterová Klára Konečná Pavel Bárta Jiří Kuneš Vladimír Kubíček Martin Doležal Marta Kučerová-Chlupáčová Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase International Journal of Molecular Sciences antimicrobial antimycobacterial benzoxaborole cytotoxicity molecular docking multidrug-resistant tuberculosis |
| title | Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase |
| title_full | Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase |
| title_fullStr | Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase |
| title_full_unstemmed | Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase |
| title_short | Design, Synthesis and Antimicrobial Evaluation of New <i>N</i>-(1-Hydroxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase |
| title_sort | design synthesis and antimicrobial evaluation of new i n i 1 hydroxy 1 3 dihydrobenzo i c i 1 2 oxaborol 6 yl hetero aryl 2 carboxamides as potential inhibitors of mycobacterial leucyl trna synthetase |
| topic | antimicrobial antimycobacterial benzoxaborole cytotoxicity molecular docking multidrug-resistant tuberculosis |
| url | https://www.mdpi.com/1422-0067/24/3/2951 |
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