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. 2022 Sep 16;87(18):12240-12249.
doi: 10.1021/acs.joc.2c01382. Epub 2022 Sep 2.

Tetramate Derivatives by Chemoselective Dieckmann Ring Closure of threo-Phenylserines and Their Antibacterial Activity

Liban Saney  1 , Kirsten E Christensen  1 , Xiang Li  1   2 , Miroslav Genov  3 , Alexander Pretsch  3 , Dagmar Pretsch  3 , Mark G Moloney  1   4
Affiliations

Tetramate Derivatives by Chemoselective Dieckmann Ring Closure of threo-Phenylserines and Their Antibacterial Activity

Liban Saney et al. J Org Chem. .

Abstract

A general route, which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclization of oxazolidines derived from threo-arylserines, is reported; the latter were found to be available by an efficient aldol-like reaction of glycine with some substituted benzaldehydes under alkaline conditions. The tetramates were found to release chelated metal cations acquired during chromatographic purification by mild acid wash. Some compounds in the library showed good antibacterial activity against Gram-positive bacteria. Cheminformatic analysis demonstrates that the most active compounds were Ro5-compliant and occupy a narrow region of chemical space, distinct from that occupied by other known antibiotics, with the most potent compounds having 399 < Mw < 530 Da; 3.5 < cLogP < 6.6; 594 < MSA <818 Å2; 9.6 < rel. PSA <13.3%. MIC values were shifted to higher concentrations when tested in the presence of HSA or blood, but was not completely abolished, consistent with a plasma protein binding (PPB) effect.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Retrosynthesis of tetramates leading to β-arylserines
Scheme 1
Scheme 1. Synthesis of β-arylserines
Scheme 2
Scheme 2. Synthesis of tetramates
Figure 2
Figure 2
X-ray structures of ethyl ester derivative 8f and carboxamidotetramate 12a.
Scheme 3
Scheme 3. Selectivity for cyclization(cis-isomer)
Scheme 4
Scheme 4. Selectivity for cyclization(trans-isomer)
Figure 3
Figure 3
Tautomeric equilibria in tetramates.
Figure 4
Figure 4
Physicochemical property space of tetramate esters 10 and amides 12–16; (a) cLogP plotted against Mw and (b) rel. PSA plotted against Mw (cLogP, MSA, and PSA were calculated using Marvin (19.9.0), 2019, ChemAxon).
Figure 5
Figure 5
Correlation of potency of tetramates against MRSA with physicochemical properties; (a) cLogP against MSA and (b) cLogP plotted against rel. PSA (cLogP, MSA, and PSA were calculated using Marvin (19.9.0), 2019, ChemAxon).
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