Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

TY - JOUR

T1 - Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

AU - Laursen, Jane B.

AU - Nielsen, John

AU - Haack, Torsten

AU - Pusuluri, Srinivas

AU - David, Sunil

AU - Balakrishna, Rajalakshmi

AU - Zeng, Yibin

AU - Ma, Zhunkun

AU - Doyle, Timothy B.

AU - Mitscher, Lester A.

PY - 2006

Y1 - 2006

N2 - A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4- dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.

AB - A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4- dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.

KW - Antimicrobial

KW - Ketodihydronicotinic acid derivatives

KW - Multiple parallel synthesis

U2 - 10.2174/138620706778700107

DO - 10.2174/138620706778700107

M3 - Journal article

C2 - 17100572

AN - SCOPUS:33750567975

SN - 1386-2073

VL - 9

SP - 663

EP - 681

JO - Combinatorial Chemistry & High Throughput Screening

JF - Combinatorial Chemistry & High Throughput Screening

IS - 9

ER -