Pyrazinecarboxylic Acid Derivatives with Antimycobacterial Activity

Doležal, Martin; Zítko, Jan; Jampílek, Josef

doi:10.5772/29598

Cited by 7 publications

(8 citation statements)

References 86 publications

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“…published several papers on synthesis and antimycobacterial activity of substituted anilides of POA, 6-Cl-POA, 5- tert- Bu-POA, and 5- tert- Bu-6-Cl-POA. The summary of structure-activity relationships within these series was published recently [9,10], including the references to original articles. The antimycobacterial activity ( M. tbc H37Rv) was indicated as percent of growth inhibition at fixed concentration of 6.25 µg/mL.…”

Section: Resultsmentioning

confidence: 99%

“…Some N -phenylpyrazine-2-carboxamides, i.e. , anilides of pyrazine-2-carboxylic acid (POA), with various substituents both on the pyrazine and phenyl core were previously described to possess significant antimycobacterial activity [9,10]. The published compounds were anilides of non-substituted pyrazine-2-carboxylic acid, 6-chloro-POA, 5- tert -butyl-POA; and 5- tert -butyl-6-chloro-POA.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides

et al. 2013

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5-Chloropyrazinamide (5-Cl-PZA) is an inhibitor of mycobacterial fatty acid synthase I with a broad spectrum of antimycobacterial activity in vitro. Some N-phenylpyrazine-2-carboxamides with different substituents on both the pyrazine and phenyl core possess significant in vitro activity against Mycobacterium tuberculosis. To test the activity of structures combining both the 5-Cl-PZA and anilide motifs a series of thirty 5-chloro-N-phenylpyrazine-2-carboxamides with various substituents R on the phenyl ring were synthesized and screened against M. tuberculosis H37Rv, M. kansasii and two strains of M. avium. Most of the compounds exerted activity against M. tuberculosis H37Rv in the range of MIC = 1.56-6.25 µg/mL and only three derivatives were inactive. The phenyl part of the molecule tolerated many different substituents while maintaining the activity. In vitro cytotoxicity was decreased in compounds with hydroxyl substituents, preferably combined with other hydrophilic substituents. 5-Chloro-N-(5-chloro-2-hydroxyphenyl)pyrazine-2-carboxamide (21) 14808(MIC = 1.56 µg/mL for M. tuberculosis; 12.5 µg/mL for other strains). 4-(5-Chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (30) preserved good activity (MIC = 3.13 µg/mL M. tuberculosis) and was rated as non-toxic in two in vitro models (Chinese hamster ovary and renal cell adenocarcinoma cell lines; SI = 47 and 35, respectively).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides

et al. 2013

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“…The studies [59,60,61] concluded that electronic (acidobasic) features of structurally different compounds notably influenced their antimicrobial effectiveness. Higher in vitro activity of variously substituted pyrazinamides against M. tuberculosis H 37 R v was connected with their relatively higher p K a s, which were calculated in silico .…”

Section: Discussionmentioning

confidence: 99%

“…Higher in vitro activity of variously substituted pyrazinamides against M. tuberculosis H 37 R v was connected with their relatively higher p K a s, which were calculated in silico . Those values led to lower ionizability of those pyrazinamide derivatives and their higher penetration to the cell [59]. In the case of diarylquinolines, which contained variously substituted N -alkylpiperazin-1-yl moiety, higher calculated basicity (p K a > 8) supported their potency against M. smegmatis [60].…”

Section: Discussionmentioning

confidence: 99%

The Structure–Antimicrobial Activity Relationships of a Promising Class of the Compounds Containing the N-Arylpiperazine Scaffold

et al. 2016

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Abstract:This research was focused on in silico characterization and in vitro biological testing of the series of the compounds carrying a N-arylpiperazine moiety. The in silico investigation was based on the prediction of electronic, steric and lipohydrophilic features. The molecules were screened against Mycobacterium avium subsp.paratuberculosis CIT03, M. smegmatis ATCC 700084, M. kansasii DSM 44162, M. marinum CAMP 5644, Staphylococcus aureus ATCC 29213, methicillin-resistant S. aureus 63718, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, Candida albicans CCM 8261, C. parapsilosis CCM 8260 and C. krusei CCM 8271, respectively, by standardized microdilution methods. The eventual antiproliferative (cytotoxic) impact of those compounds was examined on a human monocytic leukemia THP-1 cell line, as a part of the biological study. Promising potential against M. kansasii was found for 1-[3-(3-ethoxyphenylcarbamoyl)oxy-2-hydroxypropyl]-4-(3-trifluoromethylphenyl)piperazin-1-ium chloride (MIC = 31.75 µM), which was comparable to the activity of isoniazid (INH; MIC = 29.17 µM). Moreover, 1-{2-hydroxy-3-(3-methoxyphenylcarbamoyl)oxy)propyl}-4-(4-fluorophenyl)piperazin--1-ium chloride was even more effective (MIC = 17.62 µM) against given mycobacterium. Among the tested N-arylpiperazines, 1-{2-hydroxy-3-(4-methoxyphenylcarbamoyl)oxy)propyl}-4-(3-trifluoromethylphenyl)piperazin-1-ium chloride was the most efficient against M. marinum (MIC = 65.32 µM). One of the common features of all investigated substances was their insignificant antiproliferative (i.e., non-cytotoxic) effect. The study discussed structure-antimicrobial activity relationships considering electronic, steric and lipophilic properties.

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“…Our research team has already published several studies focused on structural modifications of PZA. One of our previous publication concerned a series of N-phenylpyrazine-2-carboxamides variously substituted on both aromatic rings which exerted significant antimycobacterial activity [11,12]. Further studies on 5-chloro-N-phenylpyrazine-2-carboxamides [13] and 5-alkylamino-Nphenylpyrazine-2-carboxamides [14] also showed promising results.…”

Section: Introductionmentioning

confidence: 99%

5-Alkylamino-N-phenylpyrazine-2-carboxamides: Design, Preparation, and Antimycobacterial Evaluation

et al. 2020

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According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus.

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Pyrazinecarboxylic Acid Derivatives with Antimycobacterial Activity

Cited by 7 publications

References 86 publications

Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides

Synthesis, Antimycobacterial Activity and In Vitro Cytotoxicity of 5-Chloro-N-phenylpyrazine-2-carboxamides

The Structure–Antimicrobial Activity Relationships of a Promising Class of the Compounds Containing the N-Arylpiperazine Scaffold

5-Alkylamino-N-phenylpyrazine-2-carboxamides: Design, Preparation, and Antimycobacterial Evaluation

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