Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group
Introduction: With regard to the anti-mycobacterial activity of 2-pyrazinoic acid esters (POEs), recent studies have shown that both pyrazine core and alkyl part of POE interact with the fatty acid synthase type (I) (FAS (I)) precluding a complex formation between NADPH and FAS (I). Methods: Consid...
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doaj-2bebaf1da6004212af899be59f5b5bfc2021-06-22T05:34:36ZengTabriz University of Medical SciencesBioImpacts2228-56602228-56522019-10-019419920910.15171/bi.2019.25bi-19689Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional groupHossein Khani-Meinagh0Hossein Mostafavi1Norbert Reiling2Majid Mahdavi3Gholamreza Zarrini4Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz 5166614766, IranDepartment of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz 5166614766, IranDivision of Microbial Interface Biology, Research Center Borstel, Leibniz Lung Center, Parkallee 22, D-23845 Borstel, GermanyDepartment of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, IranDepartment of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, IranIntroduction: With regard to the anti-mycobacterial activity of 2-pyrazinoic acid esters (POEs), recent studies have shown that both pyrazine core and alkyl part of POE interact with the fatty acid synthase type (I) (FAS (I)) precluding a complex formation between NADPH and FAS (I). Methods: Considering this interaction at the reductase site of FAS (I) responsible for reduction of β-ketoacyl-CoA to β-hydroxyacyl-CoA, we hypothesized that POE containing a bioreducible center in its alkyl part might show an increased anti-tubercular activity due to the involvement of FAS (I) in extra bio-reduction reaction. Thus, we synthesized novel POEs, confirmed their structures by spectral data, and subsequently evaluated their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) (H37Rv) strain at 10 μg/mL concentration. Results: Compounds 3c, 3j, and 3m showed higher activity with regard to the inhibition of Mtb growth by 45.4, 45.7, and 51.2% respectively. Unexpectedly, the maltol derived POE 3l having the lowest log p value among the POEs indicated the highest anti-mycobacterial growth activity with 56% prevention. Compounds 3c and 3l showed no remarkable cytotoxicity on human macrophages at 10 μg/mL concentration as analyzed by xCELLigence real-time cell analysis. In further experiments, some of the tested POEs, unlike pyrazinamide (PZA), exhibited significant antibacterial and also anti-fungal activities. POEs showed an enhanced bactericidal activity on gram-positive bacteria as shown for Staphylococcus aureus, e.g. compound 3b with a MIC value of 125 μg/mL but not E. coli as a gram-negative bacteria, except for maltol derived POE (3l) that showed an inverse activity in the susceptibility test. In the anticancer activity test against the human leukemia K562 cell lines using MTT assay, compounds 3e and 3j showed the highest cytotoxic effect with IC50 values of 25±8.0 μΜ and 25±5.0 μΜ, respectively. Conclusion: It was found that the majority of POEs containing a bioreducible center showed higher inhibitory activities on Mtb growth when compared to the similar compounds without a bio-reducible functional group.https://bi.tbzmed.ac.ir/PDF/bi-9-199.pdfbioreducible centercytotoxicityfatty acid biosynthesismycobacterial growth inhibition2-pyrazinoic acid ester |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hossein Khani-Meinagh Hossein Mostafavi Norbert Reiling Majid Mahdavi Gholamreza Zarrini |
spellingShingle |
Hossein Khani-Meinagh Hossein Mostafavi Norbert Reiling Majid Mahdavi Gholamreza Zarrini Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group BioImpacts bioreducible center cytotoxicity fatty acid biosynthesis mycobacterial growth inhibition 2-pyrazinoic acid ester |
author_facet |
Hossein Khani-Meinagh Hossein Mostafavi Norbert Reiling Majid Mahdavi Gholamreza Zarrini |
author_sort |
Hossein Khani-Meinagh |
title |
Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group |
title_short |
Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group |
title_full |
Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group |
title_fullStr |
Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group |
title_full_unstemmed |
Design, synthesis and evaluation of biological activities of some novel anti-TB agents with bio-reducible functional group |
title_sort |
design, synthesis and evaluation of biological activities of some novel anti-tb agents with bio-reducible functional group |
publisher |
Tabriz University of Medical Sciences |
series |
BioImpacts |
issn |
2228-5660 2228-5652 |
publishDate |
2019-10-01 |
description |
Introduction: With regard to the anti-mycobacterial activity of 2-pyrazinoic acid esters (POEs), recent studies have shown that both pyrazine core and alkyl part of POE interact with the fatty acid synthase type (I) (FAS (I)) precluding a complex formation between NADPH and FAS (I). Methods: Considering this interaction at the reductase site of FAS (I) responsible for reduction of β-ketoacyl-CoA to β-hydroxyacyl-CoA, we hypothesized that POE containing a bioreducible center in its alkyl part might show an increased anti-tubercular activity due to the involvement of FAS (I) in extra bio-reduction reaction. Thus, we synthesized novel POEs, confirmed their structures by spectral data, and subsequently evaluated their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) (H37Rv) strain at 10 μg/mL concentration. Results: Compounds 3c, 3j, and 3m showed higher activity with regard to the inhibition of Mtb growth by 45.4, 45.7, and 51.2% respectively. Unexpectedly, the maltol derived POE 3l having the lowest log p value among the POEs indicated the highest anti-mycobacterial growth activity with 56% prevention. Compounds 3c and 3l showed no remarkable cytotoxicity on human macrophages at 10 μg/mL concentration as analyzed by xCELLigence real-time cell analysis. In further experiments, some of the tested POEs, unlike pyrazinamide (PZA), exhibited significant antibacterial and also anti-fungal activities. POEs showed an enhanced bactericidal activity on gram-positive bacteria as shown for Staphylococcus aureus, e.g. compound 3b with a MIC value of 125 μg/mL but not E. coli as a gram-negative bacteria, except for maltol derived POE (3l) that showed an inverse activity in the susceptibility test. In the anticancer activity test against the human leukemia K562 cell lines using MTT assay, compounds 3e and 3j showed the highest cytotoxic effect with IC50 values of 25±8.0 μΜ and 25±5.0 μΜ, respectively. Conclusion: It was found that the majority of POEs containing a bioreducible center showed higher inhibitory activities on Mtb growth when compared to the similar compounds without a bio-reducible functional group. |
topic |
bioreducible center cytotoxicity fatty acid biosynthesis mycobacterial growth inhibition 2-pyrazinoic acid ester |
url |
https://bi.tbzmed.ac.ir/PDF/bi-9-199.pdf |
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