TY - JOUR
T1 - Synthesis and evaluation of inhibitors of Mycobacterium tuberculosis UGM using bioisosteric replacement
AU - Fu, Jian
AU - He, Ziyao
AU - Fu, Huixiao
AU - Xia, Yufen
AU - N'Go, Inès
AU - Lou, Huayong
AU - Wu, Jinglan
AU - Pan, Weidong
AU - Vincent, Stephane
N1 - Funding Information:
This study was supported by the National Science Foundation of China ( 81903517 , 32060100 ), Guizhou Provincial Science and Technology Projects, China ( [2020]1Y371 , [2021]411 , [2017]5101 ), Guiyang Municipal Science and Technology Bureau, China ( [2021]43-10) , Outstanding Chinese and Foreign Youth Exchange Program of China Association for Science and Technolog (CAST), 2019. JF and HF acknowledge the China Scholarship Council for PhD funding.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/9/1
Y1 - 2022/9/1
N2 - There is a dearth of tuberculosis (TB) drug development activity as current therapeutic treatments are inadequate due to the appearance of drug-resistant TB. The enzyme UDP-galactopyranose mutase (UGM) is involved in the biosynthesis of galactan which is essential for cell wall integrity and bacterial viability. Its inhibition has thus been featured as profitable strategy for anti-TB drug discovery. In this study, we report on the synthesis of amides derived from rosmarinic acid, their inhibitory effect towards purified UGM using three distinct biochemical assays: FP, HPLC and SPR. The rosmarinic amides generally showed a significantly higher affinity for UGM than the corresponding rosmarinic ester. In particular, compound 5h displayed interesting binding affinity values (Kd = 58 ± 7, 63 ± 9 µM towards KpUGM and MtUGM respectively). Furthermore, a new UGM SPR assay was established and confirmed that 5h binds to UGM with a dissociation constant of 104.8 ± 6.5 μM. Collectively, this study validates the amide bioisosteric strategy which has been successfully implemented to develop UGM inhibitors from rosmarinic acid, providing a substantial basis for further design of novel UGM inhibitors and anti-mycobacterial agents.
AB - There is a dearth of tuberculosis (TB) drug development activity as current therapeutic treatments are inadequate due to the appearance of drug-resistant TB. The enzyme UDP-galactopyranose mutase (UGM) is involved in the biosynthesis of galactan which is essential for cell wall integrity and bacterial viability. Its inhibition has thus been featured as profitable strategy for anti-TB drug discovery. In this study, we report on the synthesis of amides derived from rosmarinic acid, their inhibitory effect towards purified UGM using three distinct biochemical assays: FP, HPLC and SPR. The rosmarinic amides generally showed a significantly higher affinity for UGM than the corresponding rosmarinic ester. In particular, compound 5h displayed interesting binding affinity values (Kd = 58 ± 7, 63 ± 9 µM towards KpUGM and MtUGM respectively). Furthermore, a new UGM SPR assay was established and confirmed that 5h binds to UGM with a dissociation constant of 104.8 ± 6.5 μM. Collectively, this study validates the amide bioisosteric strategy which has been successfully implemented to develop UGM inhibitors from rosmarinic acid, providing a substantial basis for further design of novel UGM inhibitors and anti-mycobacterial agents.
KW - Bioisosteric replacement
KW - Enzyme activity
KW - Mycobacterium tuberculosis
KW - Rosmarinic acid derivatives
KW - UDP-galactopyranose mutase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85132894403&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2022.116896
DO - 10.1016/j.bmc.2022.116896
M3 - Article
C2 - 35777270
AN - SCOPUS:85132894403
SN - 0968-0896
VL - 69
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
M1 - 116896
ER -
