TY - JOUR
T1 - Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms
AU - Picconi, Pietro
AU - Hind, Charlotte
AU - Jamshidi, Shirin
AU - Nahar, Kazi
AU - Clifford, Melanie
AU - Wand, Matthew
AU - Sutton, J. Mark
AU - Rahman, Khondaker Miraz
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/7/27
Y1 - 2017/7/27
N2 - A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.
AB - A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.
UR - https://www.scopus.com/pages/publications/85026368329
U2 - 10.1021/acs.jmedchem.7b00108
DO - 10.1021/acs.jmedchem.7b00108
M3 - Article
C2 - 28650661
AN - SCOPUS:85026368329
SN - 0022-2623
VL - 60
SP - 6045
EP - 6059
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -