Functionalised bicyclic tetramates derived from cysteine as antibacterial agents

Abstract

Carboxamido tetramates derived from a bicyclic skeleton provide access to compounds with antibacterial activity.

Mediation of metal chelation in cysteine-derived tetramate systems

“… 68 The ranges of physiochemical properties for active tetramate derivatives were MSA of 559–737 Å 2 , MW of 427–577 Da, clogP of 1.8–6.1, clogD 7.4 of −1.7–3.7, PSA of 83–109 Å 2 and relative PSA of 12–15%. These physiochemical boundaries are comparable to antibacterial active tetramate carboxamides previously reported (MSA of 530–600 Å 2 , clogP of 1.2–2.5, clogD 7.4 of −1.1–0, PSA of 65–80 Å 2 and relative PSA of 11–14%) 30,69 and these properties also resemble those of clinically used antibacterial fluoroquinolones (MSA of 380–550 Å 2 , clogP of 0.6–3.7, clogD 7.4 of −2.7–0.5, PSA of 60–120 Å 2 and relative PSA of 13–24%). 68 The chemical space occupied by the active tetramates was further delineated by plots of clogP, clogD 7.4 , PSA and relative PSA against MW ( Fig.…”

“…spectroscopic (XPS) analysis of some derivatives clearly identi-ed the presence of Ca(II) 29 in metal-chelated tetramates and a high abundance of Ca(II), together with Na(I), Mg(II), Fe(III) and Zn(II), was also found using inductively coupled plasma mass spectrometry (ICP-MS). 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][30][31][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 cysteinederived 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 modication of the C-5 ester (CO 2 R 1 , Fig.…”

Synthetic Access to Hydrophilic Tetramate Derivatives of Cysteine

“…[10][11][12][13] New synthetic routes to these compounds continue to be developed. 10,[14][15][16][17] We have previously reported detailed investigations of bicyclic tetramates which have both demonstrated their ease of synthesis and potent antibacterial activity, at least for Gram positive systems, 18 and more recently in particular that cysteine-derived tetramate analogues with functionalisation at C-2 and C-7 are highly effective (Figure 1); 19,20 however, one key limitation of this and much of our earlier work has been the reliance on a t-butyl ring substituent which has been required for good chemical stability of intermediates, since only limited alternatives appear to be tolerated, and especially for O,N-systems. 18 However, the better stability of S,N-systems offered the possibility to move away from such highly hydrophobic substituents, but even in these cases, in vitro activities diminished when tested in presence of blood, suggesting that plasma protein binding might be impacting upon free blood concentration and hence potency.…”

α-Functionally Substituted α,β-Unsaturated Aldehydes as Fine Chemicals Reagents: Synthesis and Application

“…Subsequent oxidation of 11 with 2-iodoxybenzoic acid (IBA) in DMSO at room temperature affords 2-alkenal 12 in high yield (99%). It should be underlined that aldehyde 12 is an important building block in the synthesis of 3,5-unsubstituted 4- O -alkyl tetramates (versatile starting compounds for design of a wide variety of natural products and analogues) [ 22 , 23 ].…”