Metal binding and its amelioration in tetramates
Metal chelation in tetramates may be ameliorated by changing the ligating group and by steric blocking, which in turn leads to a change in their antibacterial properties; the former was achieved by replacement of an amide with a C-9 C═N bond and the latter by the synthesis of cysteine-derived tetram...
| প্রধান লেখক: | , , , , |
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| বিন্যাস: | Journal article |
| ভাষা: | English |
| প্রকাশিত: |
American Chemical Society
2021
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| _version_ | 1826308346339131392 |
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| author | Zhang, R Genov, M Pretsch, A Pretsch, D Moloney, MG |
| author_facet | Zhang, R Genov, M Pretsch, A Pretsch, D Moloney, MG |
| author_sort | Zhang, R |
| collection | OXFORD |
| description | Metal chelation in tetramates may be ameliorated by changing the ligating group and by steric blocking, which in turn leads to a change in their antibacterial properties; the former was achieved by replacement of an amide with a C-9 C═N bond and the latter by the synthesis of cysteine-derived tetramates with functionalization at the C-6 or C-9 enolic groups. In both cases, the metal-chelating ability was weak, and a loss of antibacterial activity was observed. Tetramate alkylations with an extended tricarbonyl-conjugated system could be achieved under Mitsunobu conditions which led to regioisomers, distinguishable by careful heteronuclear multiple bond coherence correlation and carbonyl carbon chemical shift analysis. C-9 and C-6 O-alkylation were observed but not C-8 O-alkylation for tetramate carboxamides; interestingly, C-7 alkylation with allyl and prenyl derivatives was also observed, and this arose by the rearrangement of initially formed O-alkyl products. Only the C-7 alkylated tetramate derivatives 13a and 13d with no metal-chelating ability demonstrated promising antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), with the most active analogue exhibiting a minimum inhibitory concentration of ≤ 1.95 μg/mL against MRSA, suggesting a mechanism of action independent of metal chelation. Otherwise, modifications at C-6/C-9 of tetramates led to a complete loss of metal-chelating ability, which correlated with the loss of antibacterial activity. This work further confirms that the metal-chelating capability is of fundamental importance in the biological activity of tetramates.
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| first_indexed | 2024-03-07T07:18:10Z |
| format | Journal article |
| id | oxford-uuid:42cf48bb-21a4-436b-9ea6-6162f527905c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:18:10Z |
| publishDate | 2021 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:42cf48bb-21a4-436b-9ea6-6162f527905c2022-09-06T06:31:36ZMetal binding and its amelioration in tetramatesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:42cf48bb-21a4-436b-9ea6-6162f527905cEnglishSymplectic ElementsAmerican Chemical Society2021Zhang, RGenov, MPretsch, APretsch, DMoloney, MGMetal chelation in tetramates may be ameliorated by changing the ligating group and by steric blocking, which in turn leads to a change in their antibacterial properties; the former was achieved by replacement of an amide with a C-9 C═N bond and the latter by the synthesis of cysteine-derived tetramates with functionalization at the C-6 or C-9 enolic groups. In both cases, the metal-chelating ability was weak, and a loss of antibacterial activity was observed. Tetramate alkylations with an extended tricarbonyl-conjugated system could be achieved under Mitsunobu conditions which led to regioisomers, distinguishable by careful heteronuclear multiple bond coherence correlation and carbonyl carbon chemical shift analysis. C-9 and C-6 O-alkylation were observed but not C-8 O-alkylation for tetramate carboxamides; interestingly, C-7 alkylation with allyl and prenyl derivatives was also observed, and this arose by the rearrangement of initially formed O-alkyl products. Only the C-7 alkylated tetramate derivatives 13a and 13d with no metal-chelating ability demonstrated promising antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), with the most active analogue exhibiting a minimum inhibitory concentration of ≤ 1.95 μg/mL against MRSA, suggesting a mechanism of action independent of metal chelation. Otherwise, modifications at C-6/C-9 of tetramates led to a complete loss of metal-chelating ability, which correlated with the loss of antibacterial activity. This work further confirms that the metal-chelating capability is of fundamental importance in the biological activity of tetramates. |
| spellingShingle | Zhang, R Genov, M Pretsch, A Pretsch, D Moloney, MG Metal binding and its amelioration in tetramates |
| title | Metal binding and its amelioration in tetramates |
| title_full | Metal binding and its amelioration in tetramates |
| title_fullStr | Metal binding and its amelioration in tetramates |
| title_full_unstemmed | Metal binding and its amelioration in tetramates |
| title_short | Metal binding and its amelioration in tetramates |
| title_sort | metal binding and its amelioration in tetramates |
| work_keys_str_mv | AT zhangr metalbindinganditsameliorationintetramates AT genovm metalbindinganditsameliorationintetramates AT pretscha metalbindinganditsameliorationintetramates AT pretschd metalbindinganditsameliorationintetramates AT moloneymg metalbindinganditsameliorationintetramates |