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Article

Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids

by
Lucia Semelková
1,*,
Petra Janošcová
1,
Carlos Fernandes
1,
Ghada Bouz
1,
Ondřej Janďourek
1,
Klára Konečná
1,
Pavla Paterová
2,
Lucie Navrátilová
1,
Jiří Kuneš
1,
Martin Doležal
1 and
Jan Zitko
1,*
1
Faculty of Pharmacy in Hradec Králové, Charles University, Heyrovského 1203, Hradec Králové 500 05, Czech Republic
2
Department of Clinical Microbiology, University Hospital, Sokolská 581, Hradec Králové 500 05, Czech Republic
*
Authors to whom correspondence should be addressed.
Molecules 2017, 22(9), 1491; https://doi.org/10.3390/molecules22091491
Submission received: 15 August 2017 / Accepted: 5 September 2017 / Published: 7 September 2017
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
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Abstract

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.
Keywords: anilides; antimycobacterial activity; cytotoxicity; DprE1; pyrazinamide; pyrazinoic acid; RpsA anilides; antimycobacterial activity; cytotoxicity; DprE1; pyrazinamide; pyrazinoic acid; RpsA

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MDPI and ACS Style

Semelková, L.; Janošcová, P.; Fernandes, C.; Bouz, G.; Janďourek, O.; Konečná, K.; Paterová, P.; Navrátilová, L.; Kuneš, J.; Doležal, M.; et al. Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids. Molecules 2017, 22, 1491. https://doi.org/10.3390/molecules22091491

AMA Style

Semelková L, Janošcová P, Fernandes C, Bouz G, Janďourek O, Konečná K, Paterová P, Navrátilová L, Kuneš J, Doležal M, et al. Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids. Molecules. 2017; 22(9):1491. https://doi.org/10.3390/molecules22091491

Chicago/Turabian Style

Semelková, Lucia, Petra Janošcová, Carlos Fernandes, Ghada Bouz, Ondřej Janďourek, Klára Konečná, Pavla Paterová, Lucie Navrátilová, Jiří Kuneš, Martin Doležal, and et al. 2017. "Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids" Molecules 22, no. 9: 1491. https://doi.org/10.3390/molecules22091491

APA Style

Semelková, L., Janošcová, P., Fernandes, C., Bouz, G., Janďourek, O., Konečná, K., Paterová, P., Navrátilová, L., Kuneš, J., Doležal, M., & Zitko, J. (2017). Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids. Molecules, 22(9), 1491. https://doi.org/10.3390/molecules22091491

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