Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4

Jon Kyle Awalt; Zi Kang Ooi; Trent D. Ashton; Mahta Mansouri; Petar P.S. Calic; Qingmiao Zhou; Santhya Vasanthan; Serena Lee; Katie Loi; Kate E. Jarman; Jocelyn S. Penington; Deyun Qiu; Xinxin Zhang; Adele M. Lehane; Emma Y. Mao; Maria R. Gancheva; Danny W. Wilson; Carlo Giannangelo; Christopher A. MacRaild; Darren J. Creek; Tomas Yeo; Tanaya Sheth; David A. Fidock; Alisje Churchyard; Jake Baum; Mufuliat T. Famodimu; Michael J. Delves; Mojca Kristan; Lindsay Stewart; Colin J. Sutherland; Rachael Coyle; Hannah Jagoe; Marcus C.S. Lee; Mrittika Chowdury; Tania F. de Koning-Ward; Delphine Baud; Stephen Brand; Paul F. Jackson; Alan F. Cowman; Madeline G. Dans; Brad E. Sleebs

doi:10.1021/acs.jmedchem.5c00614

Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4

Jon Kyle Awalt, Zi Kang Ooi, Trent D. Ashton, Mahta Mansouri, Petar P.S. Calic, Qingmiao Zhou, Santhya Vasanthan, Serena Lee, Katie Loi, Kate E. Jarman, Jocelyn S. Penington, Deyun Qiu, Xinxin Zhang, Adele M. Lehane, Emma Y. Mao, Maria R. Gancheva, Danny W. Wilson, Carlo Giannangelo, Christopher A. MacRaild, Darren J. CreekTomas Yeo, Tanaya Sheth, David A. Fidock, Alisje Churchyard, Jake Baum, Mufuliat T. Famodimu, Michael J. Delves, Mojca Kristan, Lindsay Stewart, Colin J. Sutherland, Rachael Coyle, Hannah Jagoe, Marcus C.S. Lee, Mrittika Chowdury, Tania F. de Koning-Ward, Delphine Baud, Stephen Brand, Paul F. Jackson, Alan F. Cowman, Madeline G. Dans^*, Brad E. Sleebs^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na⁺-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in a Plasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.

Original language	English
Pages (from-to)	8933-8966
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	8
Early online date	14 Apr 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.5c00614
Publication status	Published - 24 Apr 2025

Access to Document

10.1021/acs.jmedchem.5c00614

Cite this

Awalt, J. K., Ooi, Z. K., Ashton, T. D., Mansouri, M., Calic, P. P. S., Zhou, Q., Vasanthan, S., Lee, S., Loi, K., Jarman, K. E., Penington, J. S., Qiu, D., Zhang, X., Lehane, A. M., Mao, E. Y., Gancheva, M. R., Wilson, D. W., Giannangelo, C., MacRaild, C. A., ... Sleebs, B. E. (2025). Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4. Journal of Medicinal Chemistry, 68(8), 8933-8966. https://doi.org/10.1021/acs.jmedchem.5c00614

@article{32ae245fc0234113be6030973300cb44,

title = "Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4",

abstract = "To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na+-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in a Plasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.",

author = "Awalt, {Jon Kyle} and Ooi, {Zi Kang} and Ashton, {Trent D.} and Mahta Mansouri and Calic, {Petar P.S.} and Qingmiao Zhou and Santhya Vasanthan and Serena Lee and Katie Loi and Jarman, {Kate E.} and Penington, {Jocelyn S.} and Deyun Qiu and Xinxin Zhang and Lehane, {Adele M.} and Mao, {Emma Y.} and Gancheva, {Maria R.} and Wilson, {Danny W.} and Carlo Giannangelo and MacRaild, {Christopher A.} and Creek, {Darren J.} and Tomas Yeo and Tanaya Sheth and Fidock, {David A.} and Alisje Churchyard and Jake Baum and Famodimu, {Mufuliat T.} and Delves, {Michael J.} and Mojca Kristan and Lindsay Stewart and Sutherland, {Colin J.} and Rachael Coyle and Hannah Jagoe and Lee, {Marcus C.S.} and Mrittika Chowdury and {de Koning-Ward}, {Tania F.} and Delphine Baud and Stephen Brand and Jackson, {Paul F.} and Cowman, {Alan F.} and Dans, {Madeline G.} and Sleebs, {Brad E.}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society.",

year = "2025",

month = apr,

day = "24",

doi = "10.1021/acs.jmedchem.5c00614",

language = "English",

volume = "68",

pages = "8933--8966",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "8",

}

Awalt, JK, Ooi, ZK, Ashton, TD, Mansouri, M, Calic, PPS, Zhou, Q, Vasanthan, S, Lee, S, Loi, K, Jarman, KE, Penington, JS, Qiu, D, Zhang, X, Lehane, AM, Mao, EY, Gancheva, MR, Wilson, DW, Giannangelo, C, MacRaild, CA, Creek, DJ, Yeo, T, Sheth, T, Fidock, DA, Churchyard, A, Baum, J, Famodimu, MT, Delves, MJ, Kristan, M, Stewart, L, Sutherland, CJ, Coyle, R, Jagoe, H, Lee, MCS, Chowdury, M, de Koning-Ward, TF, Baud, D, Brand, S, Jackson, PF, Cowman, AF, Dans, MG & Sleebs, BE 2025, 'Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4', Journal of Medicinal Chemistry, vol. 68, no. 8, pp. 8933-8966. https://doi.org/10.1021/acs.jmedchem.5c00614

TY - JOUR

T1 - Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4

AU - Awalt, Jon Kyle

AU - Ooi, Zi Kang

AU - Ashton, Trent D.

AU - Mansouri, Mahta

AU - Calic, Petar P.S.

AU - Zhou, Qingmiao

AU - Vasanthan, Santhya

AU - Lee, Serena

AU - Loi, Katie

AU - Jarman, Kate E.

AU - Penington, Jocelyn S.

AU - Qiu, Deyun

AU - Zhang, Xinxin

AU - Lehane, Adele M.

AU - Mao, Emma Y.

AU - Gancheva, Maria R.

AU - Wilson, Danny W.

AU - Giannangelo, Carlo

AU - MacRaild, Christopher A.

AU - Creek, Darren J.

AU - Yeo, Tomas

AU - Sheth, Tanaya

AU - Fidock, David A.

AU - Churchyard, Alisje

AU - Baum, Jake

AU - Famodimu, Mufuliat T.

AU - Delves, Michael J.

AU - Kristan, Mojca

AU - Stewart, Lindsay

AU - Sutherland, Colin J.

AU - Coyle, Rachael

AU - Jagoe, Hannah

AU - Lee, Marcus C.S.

AU - Chowdury, Mrittika

AU - de Koning-Ward, Tania F.

AU - Baud, Delphine

AU - Brand, Stephen

AU - Jackson, Paul F.

AU - Cowman, Alan F.

AU - Dans, Madeline G.

AU - Sleebs, Brad E.

PY - 2025/4/24

Y1 - 2025/4/24

N2 - To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na+-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in a Plasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.

AB - To discover new antimalarials, a screen of the Janssen Jumpstarter library against Plasmodium falciparum uncovered the N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined and culminated in the optimized frontrunner analog WJM664, which exhibited potent asexual stage activity and high metabolic stability. Resistant selection and whole-genome sequencing revealed mutations in PfATP4, which was validated as the target by showing that analogs exhibited reduced potency against parasites with resistance-conferring mutations in PfATP4, a metabolomic signature similar to that of the PfATP4 inhibitor KAE609, and inhibition of Na+-dependent ATPase activity consistent with on-target inhibition of PfATP4. WJM664 inhibited gamete development and blocked parasite transmission to mosquitoes but exhibited low efficacy in a Plasmodium berghei mouse model, which was attributed to ATP4 species differentiation and its moderate systemic exposure. Optimization of these attributes is required for N-acetamide indoles to be pursued for development as a curative and transmission-blocking therapy.

UR - http://www.scopus.com/inward/record.url?scp=105002803601&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5c00614

DO - 10.1021/acs.jmedchem.5c00614

M3 - Article

AN - SCOPUS:105002803601

SN - 0022-2623

VL - 68

SP - 8933

EP - 8966

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

Optimization and Characterization of N-Acetamide Indoles as Antimalarials That Target PfATP4

Abstract

Access to Document

Other files and links

Fingerprint

Cite this