TY - JOUR
T1 - Novel imidazole substituted 6-methylidene-penems as broad-spectrum β-lactamase inhibitors
AU - Venkatesan, Aranapakam M.
AU - Agarwal, Atul
AU - Abe, Takao
AU - Ushirogochi, Hideki
AU - Yamamura, Itsuki
AU - Kumagai, Toshio
AU - Petersen, Peter J.
AU - Weiss, William J.
AU - Lenoy, Eileen
AU - Yang, Youjun
AU - Shlaes, David M.
AU - Ryan, John L.
AU - Mansour, Tarek S.
PY - 2004/11/15
Y1 - 2004/11/15
N2 - A series of novel imidazole substituted 6-methylidene-penems has been synthesized (R = heterocycle) and was shown to be potent, broad-spectrum β-lactamase inhibitors against class-A and class-C enzymes. The present paper deals with the design, synthesis, and structure-activity relationships (SAR) of compounds 11-15. β-Lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against β-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of β-lactam antibiotics ineffective in certain cases. To overcome resistance to β-lactam antibiotics, several β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with β-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved β-lactamase inhibitors. Although the commercially available β-lactamase inhibitor/β-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum β-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various β-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.
AB - A series of novel imidazole substituted 6-methylidene-penems has been synthesized (R = heterocycle) and was shown to be potent, broad-spectrum β-lactamase inhibitors against class-A and class-C enzymes. The present paper deals with the design, synthesis, and structure-activity relationships (SAR) of compounds 11-15. β-Lactamases are serine and metallo-dependent enzymes produced by the bacteria in defense against β-lactam antibiotics. Production of class-A, class-B, and class-C enzymes by the bacteria make the use of β-lactam antibiotics ineffective in certain cases. To overcome resistance to β-lactam antibiotics, several β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam are widely used in the clinic in combination with β-lactam antibiotics. However, single point mutations within these enzymes have allowed bacteria to overcome the inhibitory effect of the commercially approved β-lactamase inhibitors. Although the commercially available β-lactamase inhibitor/β-lactam antibiotic combinations are effective against class-A producing bacteria and many extended spectrum β-lactamase (ESBL's) producing bacteria they are less effective against class-C enzymes expressing bacteria. To circumvent this problem, based on modeling studies several novel imidazole substituted 6-methylidene-penem derivatives were synthesized and tested against various β-lactamase producing isolates. The present paper deals with the synthesis and structure-activity relationships (SAR) of these compounds.
KW - β-lactamase inhibitors
UR - http://www.scopus.com/inward/record.url?scp=6344288670&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2004.08.039
DO - 10.1016/j.bmc.2004.08.039
M3 - Article
C2 - 15498657
AN - SCOPUS:6344288670
SN - 0968-0896
VL - 12
SP - 5807
EP - 5817
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 22
ER -