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1.
Nat Chem ; 14(1): 15-24, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34903857

RESUMO

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential ß-lactamase stable ß-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.


Assuntos
Inibidores de beta-Lactamases/farmacologia , beta-Lactamas/metabolismo , Animais , Bactérias Gram-Negativas/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Ligação Proteica , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/metabolismo
2.
J Org Chem ; 76(8): 2635-47, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21410270

RESUMO

Chiral, nonracemic o-aminobenzylamines were prepared in a highly diastereoselective reduction of atropisomeric N-tert-butanesulfinylketimines. The ortho-substituent ensures the distinct reactivity of atropisomers 4d-f. The free energy of activation for atropisomerization of sulfinylimines 4d-f in THF-d(8) was determined by NMR methods to range from 70.8 to 97.9 kJ/mol.

3.
J Org Chem ; 75(7): 2357-68, 2010 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-20196622

RESUMO

Chiral, nonracemic 1,3-diamines were prepared in a highly diastereoselective reduction of diaryl N-tert-butanesulfinylketimines. Correlation between facial selectivity of the reduction and E or Z geometry of the starting ketimines suggests involvement of a cyclic transition state for the reduction. The ortho-substituent controls the geometry of N-tert-butanesulfinylketimines in the solid state and provides additional stabilization of the cyclic transition state.

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