Design, synthesis and anti-mycobacterial evaluation of some new N-phenylpyrazine-2-carboxamides

Zítko, Jan; Servusova-Vanaskova, Barbora; Paterová, Pavla; Navrátilová, Lucie; Trejtnar, František; Kuneš, Jiřı́; Doležal, Martin

doi:10.1515/chempap-2015-0246

Cited by 4 publications

(4 citation statements)

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“…The most active derivative in series 1 was 1g with R 2 = 4-OCH 3 . Generally, the most active derivatives in all series 1 , 2 and 3 follow the substitution pattern that was proposed for N -phenylpyrazine-2-carboxamides [ 19 ], that is, the benzene ring substituted with electron-withdrawing substituent in position 3 and/or electron-donating substituent in position 4.…”

Section: Resultsmentioning

confidence: 97%

“…Best compounds possessed activity with MIC at micromolar level (2–20 µM). Structure-activity relationships (SAR) in this class were reviewed elsewhere [ 17 , 18 , 19 ]. Direct inspiration for compounds presented in this paper was our previous series of 5-chloro- N -phenylpyrazine-2-carboxamides [ 18 ], which were generally more active (best compounds with MIC at low micromolar level) than previously studied 6-Cl isomers.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents

et al. 2018

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Three series of N-(pyrazin-2-yl)benzamides were designed as retro-amide analogues of previously published N-phenylpyrazine-2-carboxamides with in vitro antimycobacterial activity. The synthesized retro-amides were evaluated for in vitro growth inhibiting activity against Mycobacterium tuberculosis H37Rv (Mtb), three non-tuberculous mycobacterial strains (M. avium, M. kansasii, M. smegmatis) and selected bacterial and fungal strains of clinical importance. Regarding activity against Mtb, most N-pyrazinylbenzamides (retro-amides) possessed lower or no activity compared to the corresponding N-phenylpyrazine-2-carboxamides with the same substitution pattern. However, the active retro-amides tended to have lower HepG2 cytotoxicity and better selectivity. Derivatives with 5-chloro substitution on the pyrazine ring were generally more active compared to their 6-cloro positional isomers or non-chlorinated analogues. The best antimycobacterial activity against Mtb was found in N-(5-chloropyrazin-2-yl)benzamides with short alkyl (2h: R2 = Me; 2i: R2 = Et) in position 4 of the benzene ring (MIC = 6.25 and 3.13 µg/mL, respectively, with SI > 10). N-(5-Chloropyrazin-2-yl)benzamides with hydroxy substitution (2b: R2 = 2-OH; 2d: R2 = 4-OH) on the benzene ring or their acetylated synthetic precursors possessed the broadest spectrum of activity, being active in all three groups of mycobacterial, bacterial and fungal strains. The substantial differences in in silico calculated properties (hydrogen-bond pattern analysis, molecular electrostatic potential, HOMO and LUMO) can justify the differences in biological activities between N-pyrazinylbenzamides and N-phenylpyrazine-2-carboxamides.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents

et al. 2018

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“…Their SAR have been reviewed elsewhere. [29][30][31] The design of the title compounds of our study aimed to take the best from previously published series and incorporate the PZA fragment into a verified antiĲmyco)bacterial scaffold based on 2-aminothiazole. Three series (Scheme 1, 7-9) of hybrid compounds combining the PZA and 4-(hetero)arylthiazol-2-amine fragments were designed and synthesised.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and antimycobacterial activity of hybrid molecules combining pyrazinamide with a 4-phenylthiazol-2-amine scaffold

et al. 2018

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Hybrid compounds based on a combination of the first-line antitubercular pyrazinamide (PZA) and a formerly identified antimycobacterial scaffold of 4-arylthiazol-2-amine were designed. Eighteen compounds were prepared, characterized and tested for growth inhibition activity against H37Rv, , and by Microplate Alamar Blue Assay at neutral pH. Active compounds were tested for cytotoxicity in the human hepatocellular carcinoma cell line (HepG2). The most active 6-chloro--[4-(4-fluorophenyl)thiazol-2-yl]pyrazine-2-carboxamide (9b) also had the broadest spectrum of activity and inhibited , kansasii, and with MIC = 0.78 μg mL (2.3 μM) and a selectivity index related to HepG2 cells of SI > 20. Structure-activity relationships within the series are discussed. Based on its structural similarity to known inhibitors and the results of a molecular docking study, we suggest mycobacterial beta-ketoacyl-(acyl-carrier-protein) synthase III (FabH) as a potential target.

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“…The serious issue of AMR has driven efforts worldwide to find new therapeutic drugs Mycobacterium tuberculosis ( Mtb ) bacteria are sensitive to. An ongoing research area is the synthesis and evaluation of PZA derivatives as potential anti-TB drugs [ 5 , 6 , 7 , 8 , 9 , 10 ]. PZA is considered to be an analogue of nicotinamide and its chemical structure is closely related to INH ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Ureidopyrazine Derivatives: Synthesis and Biological Evaluation as Anti-Infectives and Abiotic Elicitors

et al. 2017

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 μg/mL, 5.19 μM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 μg/mL, 18.91 μM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.

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Design, synthesis and anti-mycobacterial evaluation of some new N-phenylpyrazine-2-carboxamides

Cited by 4 publications

References 59 publications

Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents

Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents

Design, synthesis and antimycobacterial activity of hybrid molecules combining pyrazinamide with a 4-phenylthiazol-2-amine scaffold

Ureidopyrazine Derivatives: Synthesis and Biological Evaluation as Anti-Infectives and Abiotic Elicitors

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