Metal Binding and Its Amelioration in Tetramates.
J Org Chem
; 86(18): 12886-12907, 2021 09 17.
Article
en En
| MEDLINE
| ID: mdl-34465089
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 CâN 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Staphylococcus aureus Resistente a Meticilina
Idioma:
En
Revista:
J Org Chem
Año:
2021
Tipo del documento:
Article
Pais de publicación:
Estados Unidos