Alkylamino derivatives of N-benzylpyrazine-2-carboxamide: synthesis and antimycobacterial evaluation

Servusova-Vanaskova, Barbora; Janďourek, Ondřej; Paterová, Pavla; Korduláková, Jana; Plevakova, Magdalena; Kubı́ček, Vladimı́r; Kučera, Radim; Garaj, Vladimír; Naesens, Lieve; Kuneš, Jiřı́; Doležal, Martin; Zítko, Jan

doi:10.1039/c5md00178a

Cited by 12 publications

(7 citation statements)

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“…For alkyl derivatives 9 – 12 , the antimycobacterial and antibacterial activities increase with the increase in the length of the carbon chain. This is in concordance with relationships observed in our previous series of pyrazinamide derivatives [26,27,28,29]. The most active compound against Mtb was compound 17 (phenyl derivative, R’ = 2,4-diOCH 3 ) with MIC = 12.5 µg/mL, 46 µM.…”

Section: Discussionsupporting

confidence: 90%

“…Based on our experience from the previously published series of alkylamino substituted pyrazinamide derivatives, the antimycobacterial activity was highest for compounds possessing side chains with six to eight carbons [26,27,28,29]. In the alkyl derivatives presented in this paper (compounds 9 – 12 ), octylamide (compound 12 : MIC = 25 µg/mL, 100 µM) exerted the highest activity, followed by heptylamide ( 11 : MIC = 50 µg/mL, 212 µM) and hexylamide ( 10 : MIC = 100 µg/mL, 450 µM).…”

Section: Resultsmentioning

confidence: 99%

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Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

et al. 2019

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We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

et al. 2019

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“…Based on molecular docking studies, various N -benzylpyrazine-2-carboxamides have been previously suggested as potential inhibitors of mycobacterial enoyl-ACP-reductase (InhA) [ 4 ], an essential enzyme in the synthesis of mycolic acids and the primary target of the first-line antitubercular isoniazid. In such PZA derivatives, the carbonyl oxygen of the carboxamide moiety was predicted to form an H -bond network to Tyr158 and 2′-OH of the ribose of the NAD + cofactor, which is a typical interaction pattern for most of the direct InhA inhibitors derived from triclosan [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…The percentage of new TB cases that were multidrug-resistant (MDR-TB) was 3.3% in 2014, whereas HIV-positive patients represented 12% of the 9.6 million people who developed TB [ 3 ]. Pyrazinamide (PZA), as a fist-line antitubercular drug, has gained an irreplaceable role in TB therapy and has been subjected to various chemical modifications [ 4 , 5 , 6 , 7 ]. Although PZA has been used for over sixty years [ 8 ], it is still not completely known how PZA acts in a mycobacterial cell [ 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation

et al. 2017

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A series of substituted N-benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N-benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N-(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide (1a) and N-(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide (9a) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 μg·mL−1. Compounds were screened for antibacterial activity. The most active compound was 3-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (5) against Staphylococcus aureus with MIC = 7.81 μM, and Staphylococcus epidermidis with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis. In some cases, it was capable of H-bond interactions, typical for most of the known inhibitors.

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“…This work deals with benzylamino derivatives since compounds containing a benzylamino moiety were previously reported as anti-infective substances. N -Benzylpyrazine-2-carboxamides (i.e., containing a benzylamino moiety attached to the pyrazine nucleus via a carbonyl linker) were reported by Servusova et al to show moderate antitubercular activities [ 13 , 14 , 15 ]. Benzylamino derivatives of pyrazine (with a benzylamino moiety attached directly to the pyrazine core) reported by Zitko et al and Jandourek et al showed moderate activities as well [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Pyrazinamide Derivatives Based on 3-Chloropyrazine-2-carboxamide and Their Antimicrobial Evaluation

et al. 2017

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Aminodehalogenation of 3-chloropyrazine-2-carboxamide with variously substituted benzylamines yielded a series of fifteen 3-benzylaminopyrazine-2-carboxamides. Four compounds possessed in vitro whole cell activity against Mycobacterium tuberculosis H37Rv that was at least equivalent to that of the standard pyrazinamide. MIC values ranged from 6 to 42 µM. The best MIC (6 µM) was displayed by 3-[(4-methylbenzyl)amino]pyrazine-2-carboxamide (8) that also showed low cytotoxicity in the HepG2 cell line (IC50 ≥ 250 µM). Only moderate activity against Enterococcus faecalis and Staphylococcus aureus was observed. No activity was detected against any of tested fungal strains. Molecular docking with mycobacterial enoyl-ACP reductase (InhA) was performed to investigate the possible target of the prepared compounds. Active compounds shared common binding interactions of known InhA inhibitors. Antimycobacterial activity of the title compounds was compared to the previously published benzylamino-substituted pyrazines with differing substitution on the pyrazine core (carbonitrile moiety). The title series possessed comparable activity and lower cytotoxicity than molecules containing a carbonitrile group on the pyrazine ring.

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Alkylamino derivatives of N-benzylpyrazine-2-carboxamide: synthesis and antimycobacterial evaluation

Abstract: A series of alkylamino derivatives of N-benzylpyrazine-2-carboxamide was designed, synthesized and assayed in vitro for their antimycobacterial activity.

Cited by 12 publications

References 26 publications

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, Antimicrobial Evaluation, and in Vitro Cytotoxicity

3-Substituted N-Benzylpyrazine-2-carboxamide Derivatives: Synthesis, Antimycobacterial and Antibacterial Evaluation

Synthesis of Novel Pyrazinamide Derivatives Based on 3-Chloropyrazine-2-carboxamide and Their Antimicrobial Evaluation

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