Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Rozalia A. Dodean, Papireddy Kancharla, Yuexin Li, Victor Melendez, Lisa Read, Charles E. Bane, Brian Vesely, Mara Kreishman-Deitrick, Chad Black, Qigui Li, Richard J. Sciotti, Raul Olmeda, Thu Lan Luong, Heather Gaona, Brittney Potter, Jason Sousa, Sean Marcsisin, Diana Caridha, Lisa Xie, Chau Vuong & 19 others Qiang Zeng, Jing Zhang, Ping Zhang, Hsiuling Lin, Kirk Butler, Norma Roncal, Lacy Gaynor-Ohnstad, Susan E. Leed, Christina Nolan, Stephanie J. Huezo, Stephanie A. Rasmussen, Melissa T. Stephens, John C. Tan, Roland A. Cooper, Martin J. Smilkstein, Sovitj Pou, Rolf W. Winter, Michael Riscoe, Jane X. Kelly

Research output: Contribution to journalArticle

Abstract

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Original languageEnglish (US)
Pages (from-to)3475-3502
Number of pages28
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
StatePublished - Apr 11 2019
Externally publishedYes

Fingerprint

Acridones
Antimalarials
Malaria
Plasmodium berghei
Sporozoites
Plasmodium yoelii
Liver
Human Development
Plasmodium falciparum
Structure-Activity Relationship
Libraries
Oral Administration
Hepatocytes
Parasites
Pharmacokinetics
Safety
Growth
Infection
In Vitro Techniques
acridone

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Dodean, R. A., Kancharla, P., Li, Y., Melendez, V., Read, L., Bane, C. E., ... Kelly, J. X. (2019). Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials. Journal of Medicinal Chemistry, 62(7), 3475-3502. https://doi.org/10.1021/acs.jmedchem.8b01961

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials. / Dodean, Rozalia A.; Kancharla, Papireddy; Li, Yuexin; Melendez, Victor; Read, Lisa; Bane, Charles E.; Vesely, Brian; Kreishman-Deitrick, Mara; Black, Chad; Li, Qigui; Sciotti, Richard J.; Olmeda, Raul; Luong, Thu Lan; Gaona, Heather; Potter, Brittney; Sousa, Jason; Marcsisin, Sean; Caridha, Diana; Xie, Lisa; Vuong, Chau; Zeng, Qiang; Zhang, Jing; Zhang, Ping; Lin, Hsiuling; Butler, Kirk; Roncal, Norma; Gaynor-Ohnstad, Lacy; Leed, Susan E.; Nolan, Christina; Huezo, Stephanie J.; Rasmussen, Stephanie A.; Stephens, Melissa T.; Tan, John C.; Cooper, Roland A.; Smilkstein, Martin J.; Pou, Sovitj; Winter, Rolf W.; Riscoe, Michael; Kelly, Jane X.

In: Journal of Medicinal Chemistry, Vol. 62, No. 7, 11.04.2019, p. 3475-3502.

Research output: Contribution to journalArticle

Dodean, RA, Kancharla, P, Li, Y, Melendez, V, Read, L, Bane, CE, Vesely, B, Kreishman-Deitrick, M, Black, C, Li, Q, Sciotti, RJ, Olmeda, R, Luong, TL, Gaona, H, Potter, B, Sousa, J, Marcsisin, S, Caridha, D, Xie, L, Vuong, C, Zeng, Q, Zhang, J, Zhang, P, Lin, H, Butler, K, Roncal, N, Gaynor-Ohnstad, L, Leed, SE, Nolan, C, Huezo, SJ, Rasmussen, SA, Stephens, MT, Tan, JC, Cooper, RA, Smilkstein, MJ, Pou, S, Winter, RW, Riscoe, M & Kelly, JX 2019, 'Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials', Journal of Medicinal Chemistry, vol. 62, no. 7, pp. 3475-3502. https://doi.org/10.1021/acs.jmedchem.8b01961
Dodean, Rozalia A. ; Kancharla, Papireddy ; Li, Yuexin ; Melendez, Victor ; Read, Lisa ; Bane, Charles E. ; Vesely, Brian ; Kreishman-Deitrick, Mara ; Black, Chad ; Li, Qigui ; Sciotti, Richard J. ; Olmeda, Raul ; Luong, Thu Lan ; Gaona, Heather ; Potter, Brittney ; Sousa, Jason ; Marcsisin, Sean ; Caridha, Diana ; Xie, Lisa ; Vuong, Chau ; Zeng, Qiang ; Zhang, Jing ; Zhang, Ping ; Lin, Hsiuling ; Butler, Kirk ; Roncal, Norma ; Gaynor-Ohnstad, Lacy ; Leed, Susan E. ; Nolan, Christina ; Huezo, Stephanie J. ; Rasmussen, Stephanie A. ; Stephens, Melissa T. ; Tan, John C. ; Cooper, Roland A. ; Smilkstein, Martin J. ; Pou, Sovitj ; Winter, Rolf W. ; Riscoe, Michael ; Kelly, Jane X. / Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 7. pp. 3475-3502.
@article{c5ccbf3e4e0f4de58bf7e1511d157730,
title = "Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials",
abstract = "Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.",
author = "Dodean, {Rozalia A.} and Papireddy Kancharla and Yuexin Li and Victor Melendez and Lisa Read and Bane, {Charles E.} and Brian Vesely and Mara Kreishman-Deitrick and Chad Black and Qigui Li and Sciotti, {Richard J.} and Raul Olmeda and Luong, {Thu Lan} and Heather Gaona and Brittney Potter and Jason Sousa and Sean Marcsisin and Diana Caridha and Lisa Xie and Chau Vuong and Qiang Zeng and Jing Zhang and Ping Zhang and Hsiuling Lin and Kirk Butler and Norma Roncal and Lacy Gaynor-Ohnstad and Leed, {Susan E.} and Christina Nolan and Huezo, {Stephanie J.} and Rasmussen, {Stephanie A.} and Stephens, {Melissa T.} and Tan, {John C.} and Cooper, {Roland A.} and Smilkstein, {Martin J.} and Sovitj Pou and Winter, {Rolf W.} and Michael Riscoe and Kelly, {Jane X.}",
year = "2019",
month = "4",
day = "11",
doi = "10.1021/acs.jmedchem.8b01961",
language = "English (US)",
volume = "62",
pages = "3475--3502",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

AU - Dodean, Rozalia A.

AU - Kancharla, Papireddy

AU - Li, Yuexin

AU - Melendez, Victor

AU - Read, Lisa

AU - Bane, Charles E.

AU - Vesely, Brian

AU - Kreishman-Deitrick, Mara

AU - Black, Chad

AU - Li, Qigui

AU - Sciotti, Richard J.

AU - Olmeda, Raul

AU - Luong, Thu Lan

AU - Gaona, Heather

AU - Potter, Brittney

AU - Sousa, Jason

AU - Marcsisin, Sean

AU - Caridha, Diana

AU - Xie, Lisa

AU - Vuong, Chau

AU - Zeng, Qiang

AU - Zhang, Jing

AU - Zhang, Ping

AU - Lin, Hsiuling

AU - Butler, Kirk

AU - Roncal, Norma

AU - Gaynor-Ohnstad, Lacy

AU - Leed, Susan E.

AU - Nolan, Christina

AU - Huezo, Stephanie J.

AU - Rasmussen, Stephanie A.

AU - Stephens, Melissa T.

AU - Tan, John C.

AU - Cooper, Roland A.

AU - Smilkstein, Martin J.

AU - Pou, Sovitj

AU - Winter, Rolf W.

AU - Riscoe, Michael

AU - Kelly, Jane X.

PY - 2019/4/11

Y1 - 2019/4/11

N2 - Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

AB - Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

UR - http://www.scopus.com/inward/record.url?scp=85063396858&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063396858&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.8b01961

DO - 10.1021/acs.jmedchem.8b01961

M3 - Article

VL - 62

SP - 3475

EP - 3502

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -