Cargando…
Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents
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 H...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225228/ https://www.ncbi.nlm.nih.gov/pubmed/30231544 http://dx.doi.org/10.3390/molecules23092390 |
_version_ | 1783369727826984960 |
---|---|
author | Zitko, Jan Mindlová, Alžběta Valášek, Ondřej Jand’ourek, Ondřej Paterová, Pavla Janoušek, Jiří Konečná, Klára Doležal, Martin |
author_facet | Zitko, Jan Mindlová, Alžběta Valášek, Ondřej Jand’ourek, Ondřej Paterová, Pavla Janoušek, Jiří Konečná, Klára Doležal, Martin |
author_sort | Zitko, Jan |
collection | PubMed |
description | 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: R(2) = Me; 2i: R(2) = 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: R(2) = 2-OH; 2d: R(2) = 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. |
format | Online Article Text |
id | pubmed-6225228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62252282018-11-13 Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents Zitko, Jan Mindlová, Alžběta Valášek, Ondřej Jand’ourek, Ondřej Paterová, Pavla Janoušek, Jiří Konečná, Klára Doležal, Martin Molecules Article 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: R(2) = Me; 2i: R(2) = 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: R(2) = 2-OH; 2d: R(2) = 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. MDPI 2018-09-18 /pmc/articles/PMC6225228/ /pubmed/30231544 http://dx.doi.org/10.3390/molecules23092390 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zitko, Jan Mindlová, Alžběta Valášek, Ondřej Jand’ourek, Ondřej Paterová, Pavla Janoušek, Jiří Konečná, Klára Doležal, Martin Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents |
title | Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents |
title_full | Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents |
title_fullStr | Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents |
title_full_unstemmed | Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents |
title_short | Design, Synthesis and Evaluation of N-pyrazinylbenzamides as Potential Antimycobacterial Agents |
title_sort | design, synthesis and evaluation of n-pyrazinylbenzamides as potential antimycobacterial agents |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225228/ https://www.ncbi.nlm.nih.gov/pubmed/30231544 http://dx.doi.org/10.3390/molecules23092390 |
work_keys_str_mv | AT zitkojan designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT mindlovaalzbeta designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT valasekondrej designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT jandourekondrej designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT paterovapavla designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT janousekjiri designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT konecnaklara designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents AT dolezalmartin designsynthesisandevaluationofnpyrazinylbenzamidesaspotentialantimycobacterialagents |