TY - JOUR
T1 - Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth
AU - Ray, Peter C.
AU - Huggett, Margaret
AU - Turner, Penelope A.
AU - Taylor, Malcolm
AU - Cleghorn, Laura A.T.
AU - Early, Julie
AU - Kumar, Anuradha
AU - Bonnett, Shilah A.
AU - Flint, Lindsay
AU - Joerss, Douglas
AU - Johnson, James
AU - Korkegian, Aaron
AU - Mullen, Steven
AU - Moure, Abraham L.
AU - Davis, Susan H.
AU - Murugesan, Dinakaran
AU - Mathieson, Michael
AU - Caldwell, Nicola
AU - Engelhart, Curtis A.
AU - Schnappinger, Dirk
AU - Epemolu, Ola
AU - Zuccotto, Fabio
AU - Riley, Jennifer
AU - Scullion, Paul
AU - Stojanovski, Laste
AU - Massoudi, Lisa
AU - Robertson, Gregory T.
AU - Lenaerts, Anne J.
AU - Freiberg, Gail
AU - Kempf, Dale J.
AU - Masquelin, Thierry
AU - Hipskind, Philip A.
AU - Odingo, Joshua
AU - Read, Kevin D.
AU - Green, Simon R.
AU - Wyatt, Paul G.
AU - Parish, Tanya
N1 - Funding Information:
We thank Lucy Ellis, Fred Simeons, Yoko Shishikura, Liam Ferguson, Lorna Campbell, James Roberts, Susan Lawrie, Alex Cookson, Kirsty Cookson, Emma Gutcher, Desiree Zeller, James Ahn, Torey Alling, Lena Anoshchenko, Bryan Grogan, Megha Gupta, Junitta Guzman, Yulia Ovechkina, David Roberts, Catherine Shelton, Bjorn Sunde, Dean Thompson, and Anisa Tracy for technical assistance. This work was funded in part by an award to P.G.W. from the Bill and Melinda Gates Foundation (OPP1066891) and Wellcome Trust (100195/Z/12/Z); by awards from BMG&F to T.P. (OPP1024038) and A.J.L./G.T.R. (OPP1126594); by Eli Lilly and Company in support of the mission of the Lilly TB Drug Discovery Initiative; and an award to T.P. by NIAID of the National Institutes of Health (R01AI099188). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/1/26
Y1 - 2021/1/26
N2 - With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.
AB - With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles (1-2) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29, with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29, and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis. Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time.
UR - http://www.scopus.com/inward/record.url?scp=85099972111&partnerID=8YFLogxK
U2 - 10.1021/acsomega.0c05589
DO - 10.1021/acsomega.0c05589
M3 - Article
C2 - 33521468
AN - SCOPUS:85099972111
SN - 2470-1343
VL - 6
SP - 2284
EP - 2311
JO - ACS Omega
JF - ACS Omega
IS - 3
ER -