Metal Binding and Its Amelioration in Tetramates

Abstract

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.

Mediation of metal chelation in cysteine-derived tetramate systems

“…Interestingly, unlike C-6/C-9 modified tetramates, 34 reduced metal chelation ability in the C-5 modified tetramates did not result in a loss of antibacterial activity. Those C-5 modified tetramates that showed some antibacterial activity with MIC values against MRSA ≤ 62.5 μg ml −1 were selected, and their MIC values plotted against post-column peak broadening ( W 1/2 /Hz of the H-2 signal) ( Fig.…”

“…The best combination for reducing metal chelation was 58 with C-9 cyclohexyl ketone pendant and C-5 benzyl ester, with a post-column H-2 width at 2.4 Hz, which is almost as sharp as non-metal binding tetramates. 34 …”

“…While there is evidence of reduced metal chelation in these tetramate systems, it clearly does not compromise their antibacterial activity, which is in contrast with our previous attempt to directly block metal complexation. 34 However, complete loss of activity in the presence of serum/blood was found, likely due to plasma protein binding due to relatively high lipophilicity ( Table 7 ). This outcome highlights the challenge in antibacterial drug discovery of simultaneous multiparametric optimization, including consideration of at least efficacy, toxicity, membrane permeability and plasma binding.…”

“… 30 The metal chelating properties of tetramates are most immediately evident by post-chromatographic signal broadening in 1 H NMR spectra, which can only be removed by acid wash, 29–32 and the metal complexation behaviour of tetramates was also found to be both structure and metal-ion dependent. 33 We have described earlier that cysteine-derived bicyclic tetramates 1 are excellent metal chelating agents, and established that the C-6, C-8 and/or C-9 carbonyl groups were directly involved in that metal complexation, but that it could be blocked by protection of the enolic system; 34 it seemed that modification of the C-5 ester (CO 2 R 1 , Fig. 1 ), along with the concave-convex shape of the bicyclic tetramate system, might be further exploited to alter the metal binding ability of the tetramate system by steric interference distal to the region of metal chelation.…”

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

“…Along with, e.g., polyphenols and quinones, the search yielded 3-acyltetramic and tetronic acids (and their derivatives), which demonstrated activities against multidrug-resistant bacteria [ 72 ]. Their antibacterial actions are shown to be directly correlated to their chelating ability [ 73 ]. As opposed to simpler fungal tetramates, bacteria tend to produce a polycyclic tetramate macrolactams (PTM), which are especially promising ( Figure 13 a) [ 74 ].…”