Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids
Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form...
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MDPI AG
2017-09-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/22/9/1491 |
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| author | Lucia Semelková Petra Janošcová Carlos Fernandes Ghada Bouz Ondřej Janďourek Klára Konečná Pavla Paterová Lucie Navrátilová Jiří Kuneš Martin Doležal Jan Zitko |
| author_facet | Lucia Semelková Petra Janošcová Carlos Fernandes Ghada Bouz Ondřej Janďourek Klára Konečná Pavla Paterová Lucie Navrátilová Jiří Kuneš Martin Doležal Jan Zitko |
| author_sort | Lucia Semelková |
| collection | DOAJ |
| description | Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL−1 (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL−1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding. |
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| language | English |
| last_indexed | 2024-12-11T08:50:43Z |
| publishDate | 2017-09-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a5bc6c58eae3496fac72329e6e6f1ccf2022-12-22T01:14:02ZengMDPI AGMolecules1420-30492017-09-01229149110.3390/molecules22091491molecules22091491Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic AcidsLucia Semelková0Petra Janošcová1Carlos Fernandes2Ghada Bouz3Ondřej Janďourek4Klára Konečná5Pavla Paterová6Lucie Navrátilová7Jiří Kuneš8Martin Doležal9Jan Zitko10Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicDepartment of Clinical Microbiology, University Hospital, Sokolská 581, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicFaculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech RepublicPyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL−1 (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL−1. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding.https://www.mdpi.com/1420-3049/22/9/1491anilidesantimycobacterial activitycytotoxicityDprE1pyrazinamidepyrazinoic acidRpsA |
| spellingShingle | Lucia Semelková Petra Janošcová Carlos Fernandes Ghada Bouz Ondřej Janďourek Klára Konečná Pavla Paterová Lucie Navrátilová Jiří Kuneš Martin Doležal Jan Zitko Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids Molecules anilides antimycobacterial activity cytotoxicity DprE1 pyrazinamide pyrazinoic acid RpsA |
| title | Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids |
| title_full | Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids |
| title_fullStr | Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids |
| title_full_unstemmed | Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids |
| title_short | Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids |
| title_sort | design synthesis antimycobacterial evaluation and in silico studies of 3 phenylcarbamoyl pyrazine 2 carboxylic acids |
| topic | anilides antimycobacterial activity cytotoxicity DprE1 pyrazinamide pyrazinoic acid RpsA |
| url | https://www.mdpi.com/1420-3049/22/9/1491 |
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