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Article

Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity

by
Vinod Sukanth Kumar Pallabothula
1,*,
Marek Kerda
1,
Martin Juhás
1,
Ondřej Janďourek
1,
Klára Konečná
1,
Pavel Bárta
1,
Pavla Paterová
2 and
Jan Zitko
1,*
1
Faculty of Pharmacy in Hradec Králové, Charles University, Ak. Heyrovského 1203/8, 500 05 Hradec Králové, Czech Republic
2
Department of Clinical Microbiology, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic
*
Authors to whom correspondence should be addressed.
Biomolecules 2022, 12(11), 1561; https://doi.org/10.3390/biom12111561
Submission received: 25 September 2022 / Revised: 11 October 2022 / Accepted: 13 October 2022 / Published: 26 October 2022
(This article belongs to the Collection Feature Papers in Chemical Biology)
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Abstract

Multidrug-resistant tuberculosis (MDR-TB) poses a significant threat to mankind and as such earned its place on the WHO list of priority pathogens. New antimycobacterials with a mechanism of action different to currently used agents are highly required. This study presents the design, synthesis, and biological evaluation of 3-acylaminopyrazine-2-carboxamides derived from a previously reported inhibitor of human prolyl-tRNA synthetase. Compounds were evaluated in vitro against various strains of mycobacteria, pathogenic bacteria, and fungi of clinical significance. In general, high activity against mycobacteria was noted, while the antibacterial and antifungal activity was minimal. The most active compounds were 4’-substituted 3-(benzamido)pyrazine-2-carboxamides, exerting MIC (Minimum Inhibitory Concentration) from 1.95 to 31.25 µg/mL. Detailed structure–activity relationships were established and rationalized in silico with regard to mycobacterial ProRS as a probable target. The active compounds preserved their activity even against multidrug-resistant strains of Mycobacterium tuberculosis. At the same time, they were non-cytotoxic against HepG2 human hepatocellular carcinoma cells. This project is the first step in the successful repurposing of inhibitors of human ProRS to inhibitors of mycobacterial ProRS with antimycobacterial activity.
Keywords: 3-aminopyrazinamide; antibacterial; antimycobacterial; homology model; molecular dynamics; prolyl-tRNA synthetase; repurposing; tuberculosis 3-aminopyrazinamide; antibacterial; antimycobacterial; homology model; molecular dynamics; prolyl-tRNA synthetase; repurposing; tuberculosis

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MDPI and ACS Style

Pallabothula, V.S.K.; Kerda, M.; Juhás, M.; Janďourek, O.; Konečná, K.; Bárta, P.; Paterová, P.; Zitko, J. Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity. Biomolecules 2022, 12, 1561. https://doi.org/10.3390/biom12111561

AMA Style

Pallabothula VSK, Kerda M, Juhás M, Janďourek O, Konečná K, Bárta P, Paterová P, Zitko J. Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity. Biomolecules. 2022; 12(11):1561. https://doi.org/10.3390/biom12111561

Chicago/Turabian Style

Pallabothula, Vinod Sukanth Kumar, Marek Kerda, Martin Juhás, Ondřej Janďourek, Klára Konečná, Pavel Bárta, Pavla Paterová, and Jan Zitko. 2022. "Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity" Biomolecules 12, no. 11: 1561. https://doi.org/10.3390/biom12111561

APA Style

Pallabothula, V. S. K., Kerda, M., Juhás, M., Janďourek, O., Konečná, K., Bárta, P., Paterová, P., & Zitko, J. (2022). Adenosine-Mimicking Derivatives of 3-Aminopyrazine-2-Carboxamide: Towards Inhibitors of Prolyl-tRNA Synthetase with Antimycobacterial Activity. Biomolecules, 12(11), 1561. https://doi.org/10.3390/biom12111561

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