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; 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 K. Riscoe; Jane X. Kelly

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 VuongQiang 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 K. Riscoe, Jane X. Kelly

Department of Natural Sciences and Mathematics

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

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 language	American English
Pages (from-to)	3475-3502
Number of pages	28
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	7
State	Published - Apr 11 2019

Funding

Funders	Funder number
U.S. Department of Veterans Affairs	I01BX001421

ASJC Scopus Subject Areas

Molecular Medicine
Drug Discovery

Keywords

Acridones
Animals
Antimalarials
Disease Models
Animal
Drug Discovery
Hep G2 Cells
Humans
Malaria
Mice
Plasmodium
Species Specificity
Structure-Activity Relationship
Drug Discovery/methods
Acridones/chemistry
Malaria/drug therapy
Plasmodium/classification
Antimalarials/chemistry
Disease Models, Animal

Disciplines

Life Sciences
Physical Sciences and Mathematics

Access to Document

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822569/

OpenUrl availability

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Dodean, R. A., Kancharla, P., Li, Y., Melendez, V., Read, L., Bane, C. E., Vesely, B., Kreishman-Deitrick, M., Black, C., Li, Q., Sciotti, R. J., Olmeda, R., Luong, T.-L., Gaona, H., Potter, B., Sousa, J., Marcsisin, S., Caridha, D., Xie, L., ... Kelly, J. X. (2019). Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials. Journal of Medicinal Chemistry, 62(7), 3475-3502. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822569/

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, T-L, 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, MK & 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822569/>

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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.",

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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 Thu-Lan Luong 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 Riscoe, \{Michael K.\} and Kelly, \{Jane X.\}",

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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 K.

AU - Kelly, Jane X.

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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.

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KW - Animals

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KW - Disease Models

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KW - Drug Discovery

KW - Hep G2 Cells

KW - Humans

KW - Malaria

KW - Mice

KW - Plasmodium

KW - Species Specificity

KW - Structure-Activity Relationship

KW - Drug Discovery/methods

KW - Acridones/chemistry

KW - Malaria/drug therapy

KW - Plasmodium/classification

KW - Antimalarials/chemistry

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UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/32

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M3 - Article

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SP - 3475

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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ER -

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Abstract

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

OpenUrl availability

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Cite this