Synthesis of fused tetramate-oxazolidine and -imidazolidine derivatives and their antibacterial activity.

A chemoselective route which provides direct access to bicyclic tetramates, making use of Dieckmann cyclisation of functionalised oxazolidines and imidazolidines derived from an aminomalonate, is reported; calculations suggest that the observed chemoselectivity is kinetically controlled and leads to the thermodynamically most stable product. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria, and this activity is maximal in a well-defined region of chemical space (554 < Mw < 722 g mol-1; 5.78 < cLogP < 7.16; 788 < MSA < 972 Å2; 10.3 < rel. PSA < 19.08).

Tetramate derivatives by chemoselective Dieckmann ring closure of allo-phenylserines, and their antibacterial activity.

A general route which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclisation of oxazolidine derivatives derived from allo-phenylserines, is reported. Of interest is the high level of diastereoselectivity observed for the N-acylation reaction of oxazolidines and the complete chemoselectivity of their ring closure in the Dieckmann cyclisation. Significantly, the sense of the chemoselectivity is different to earlier reported threo-phenylserine systems, showing the importance of steric bulk around the bicyclic ring system. The derived C7-carboxamidotetramates, but not C7-acyl systems, exhibited potent antibacterial activity against MRSA, with the most active compounds exhibiting well-defined physicochemical and structure-activity properties. This work clearly demonstrates that densely functionalised tetramates are both readily available and may exhibit high levels of antibacterial activity.

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

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.