Scaffold Morphing To Identify Novel DprE1 Inhibitors
with Antimycobacterial Activity
Posted on 2019-09-27 - 15:05
We report a novel
benzimidazole (BI) based DprE1 inhibitor that
resulted from scaffold morphing of a 1,4-azaindole series. The clinical
progression of the 1,4-azaindole series from our previous work validates
the potential of exploring newer chemical entities with antimycobacterial
activity driven via a noncovalent inhibition of the decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1). The representative compounds
from the new scaffold reported in this study exhibited an improved
solubility and higher free plasma fraction, while retaining potent
DprE1 inhibition and antimycobacterial activity. A representative
compound from the benzimidazole series demonstrated good efficacy
in a murine model of tuberculosis. Furthermore, molecular modeling
of the BI scaffold suggests plausible modes of binding in the active
site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.
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R, Manjunatha
M.; Shandil, Radha; Panda, Manoranjan; Sadler, Claire; Ambady, Anisha; Panduga, Vijender; et al. (2019). Scaffold Morphing To Identify Novel DprE1 Inhibitors
with Antimycobacterial Activity. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.9b00343
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AUTHORS (23)
MR
Manjunatha
M. R
RS
Radha Shandil
MP
Manoranjan Panda
CS
Claire Sadler
AA
Anisha Ambady
VP
Vijender Panduga
NK
Naveen Kumar
JM
Jyothi Mahadevaswamy
MS
M. Sreenivasaiah
AN
Ashwini Narayan
SG
Supreeth Guptha
SS
Sreevalli Sharma
VS
Vasan K. Sambandamurthy
VR
Vasanthi Ramachandran
MM
Meenakshi Mallya
CC
Christopher Cooper
KM
Khisi Mdluli
SB
Scott Butler
RT
Ruben Tommasi
PI
Pravin S. Iyer