TY - JOUR
T1 - Design, synthesis and evaluation of a series of 5-methoxy-2,3-naphthalimide derivatives as AcrB inhibitors for the reversal of bacterial resistance
AU - Jin, Chaobin
AU - Alenazy, Rawaf
AU - Wang, Yinhu
AU - Mowla, Rumana
AU - Qin, Yinhui
AU - Tan, Jin Quan Eugene
AU - Modi, Natansh Deepak
AU - Gu, Xinjie
AU - Polyak, Steven W.
AU - Venter, Henrietta
AU - Ma, Shutao
PY - 2019/4/1
Y1 - 2019/4/1
N2 - A series of novel 5-methoxy-2,3-naphthalimide derivatives were designed, synthesized and evaluated for their biological activities. In particular, the ability of the compounds to synergize with antimicrobials, to inhibit Nile Red efflux, and to target AcrB was assayed. The results showed that the most of the tested compounds more sensitized the Escherichia coli BW25113 to the antibiotics than the parent compounds 7c and 15, which were able to inhibit Nile Red efflux. Significantly, compound A5 possessed the most potent antibacterial synergizing activity in combination with levofloxacin by 4 times and 16 times at the concentration of 8 and 16 µg/mL, respectively, whilst A5 could effectively abolish Nile Red efflux at 100 μM. Additionally, target effect of A5 was confirmed in the outer- or inner membrane permeabilization assays. Therefore, A5 is an excellent lead compound for further structural optimization.
AB - A series of novel 5-methoxy-2,3-naphthalimide derivatives were designed, synthesized and evaluated for their biological activities. In particular, the ability of the compounds to synergize with antimicrobials, to inhibit Nile Red efflux, and to target AcrB was assayed. The results showed that the most of the tested compounds more sensitized the Escherichia coli BW25113 to the antibiotics than the parent compounds 7c and 15, which were able to inhibit Nile Red efflux. Significantly, compound A5 possessed the most potent antibacterial synergizing activity in combination with levofloxacin by 4 times and 16 times at the concentration of 8 and 16 µg/mL, respectively, whilst A5 could effectively abolish Nile Red efflux at 100 μM. Additionally, target effect of A5 was confirmed in the outer- or inner membrane permeabilization assays. Therefore, A5 is an excellent lead compound for further structural optimization.
KW - 5-Methoxy-2,3-naphthalimide
KW - AcrB
KW - Antimicrobial resistance
KW - Efflux pump inhibitor
KW - Inhibition of efflux
KW - Synergism
UR - http://www.scopus.com/inward/record.url?scp=85061199529&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1147538
U2 - 10.1016/j.bmcl.2019.02.003
DO - 10.1016/j.bmcl.2019.02.003
M3 - Article
C2 - 30755336
AN - SCOPUS:85061199529
SN - 0960-894X
VL - 29
SP - 882
EP - 889
JO - Bioorganic & Medicinal Chemistry Letters
JF - Bioorganic & Medicinal Chemistry Letters
IS - 7
ER -