Design, synthesis and biological evaluation of α-substituted isonipecotic acid benzothiazole analogues as potent bacterial type II topoisomerase inhibitors.
The discovery and optimisation of a new class of benzothiazole small molecules that inhibit bacterial DNA gyrase and topoisomerase IV are described. Antibacterial properties have been demonstrated by activity against DNA gyrase ATPase and potent activity against Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes and Haemophilus influenzae. Further refinements to the scaffold designed to enhance drug-likeness included analogues bearing an α-substituent to the carboxylic acid group, resulting in excellent solubility and favourable pharmacokinetic properties.
Biota Holdings Ltd, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia. Electronic address: l.offermann@biota.com.au.
Lorraine C
LC
Axford
Piyush K
PK
Agarwal
Kelly H
KH
Anderson
Laura N
LN
Andrau
John
J
Atherall
Stephanie
S
Barker
James M
JM
Bennett
Michael
M
Blair
Ian
I
Collins
Lloyd G
LG
Czaplewski
David T
DT
Davies
Carlie T
CT
Gannon
Dushyant
D
Kumar
Paul
P
Lancett
Alastair
A
Logan
Christopher J
CJ
Lunniss
Dale R
DR
Mitchell
Daniel A
DA
Offermann
James T
JT
Palmer
Nicholas
N
Palmer
Gary R W
GR
Pitt
Stéphanie
S
Pommier
Daniel
D
Price
B
B
Narasinga Rao
Rashmi
R
Saxena
Tarun
T
Shukla
Amit K
AK
Singh
Mahipal
M
Singh
Anil
A
Srivastava
Christopher
C
Steele
Neil R
NR
Stokes
Helena B
HB
Thomaides-Brears
Edward M
EM
Tyndall
David
D
Watson
David J
DJ
Haydon
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D013293:Enterococcus faecalis / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology; D006207:Half-Life; D007540:Isonipecotic Acids / Q000737:chemistry*; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000201:enzymology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D007540:Isonipecotic Acids; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; C005465:benzothiazole
Antibacterial; DNA gyrase; Topoisomerase