Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

Papireddy Kancharla; Rozalia A. Dodean; Yuexin Li; Sovitj Pou; Brandon Pybus; 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; Frida G. Ceja; Stephanie A. Rasmussen; Patrick K. Tumwebaze; Philip J. Rosenthal; Jianbing Mu; Brett R. Bayles; Roland A. Cooper; Kevin A. Reynolds; Martin J. Smilkstein; Michael K. Riscoe; Jane X. Kelly

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

Papireddy Kancharla, Rozalia A. Dodean, Yuexin Li, Sovitj Pou, Brandon Pybus, 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 CaridhaLisa Xie, Chau Vuong, Qiang Zeng, Jing Zhang, Ping Zhang, Hsiuling Lin, Kirk Butler, Norma Roncal, Lacy Gaynor-Ohnstad, Susan E. Leed, Christina Nolan, Frida G. Ceja, Stephanie A. Rasmussen, Patrick K. Tumwebaze, Philip J. Rosenthal, Jianbing Mu, Brett R. Bayles, Roland A. Cooper, Kevin A. Reynolds, Martin J. Smilkstein, Michael K. Riscoe, Jane X. Kelly

Department of Natural Sciences and Mathematics

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

Abstract

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

Original language	American English
Pages (from-to)	6179-6202
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	11
State	Published - Jun 11 2020

Funding

This project was supported by NIH/NIAID (award 1R01AI093784) and DOD/PRMRP (award PR160693/W81XWH-17-2-0041). The material has been reviewed by the Walter Reed Army Institute of Research (WRAIR). There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the true views of the Department of the Army or the Department of Defense. Research was conducted in AAALAC-accredited facilities in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals (NRC Publication).

Funders	Funder number
PRMRP	PR160693/W81XWH-17-2-0041
National Institutes of Health
U.S. Department of Defense
National Institute of Allergy and Infectious Diseases	R01AI093784

ASJC Scopus Subject Areas

Molecular Medicine
Drug Discovery

Keywords

Administration, Oral
Humans
Mice, Inbred C57BL
Acridones/chemistry
Half-Life
Male
Structure-Activity Relationship
Cell Survival/drug effects
Life Cycle Stages/drug effects
Malaria/drug therapy
Hep G2 Cells
Plasmodium falciparum/drug effects
Animals
Female
Mice
Antimalarials/chemistry
Disease Models, Animal

Disciplines

Life Sciences
Physical Sciences and Mathematics

Access to Document

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354843/

OpenUrl availability

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Kancharla, P., Dodean, R. A., Li, Y., Pou, S., Pybus, B., 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., ... Kelly, J. X. (2020). Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials. Journal of Medicinal Chemistry, 63(11), 6179-6202. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354843/

Kancharla, P, Dodean, RA, Li, Y, Pou, S, Pybus, B, 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, Ceja, FG, Rasmussen, SA, Tumwebaze, PK, Rosenthal, PJ, Mu, J, Bayles, BR, Cooper, RA, Reynolds, KA, Smilkstein, MJ, Riscoe, MK & Kelly, JX 2020, 'Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.', Journal of Medicinal Chemistry, vol. 63, no. 11, pp. 6179-6202. <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354843/>

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AU - Kancharla, Papireddy

AU - Dodean, Rozalia A.

AU - Li, Yuexin

AU - Pou, Sovitj

AU - Pybus, Brandon

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 - Ceja, Frida G.

AU - Rasmussen, Stephanie A.

AU - Tumwebaze, Patrick K.

AU - Rosenthal, Philip J.

AU - Mu, Jianbing

AU - Bayles, Brett R.

AU - Cooper, Roland A.

AU - Reynolds, Kevin A.

AU - Smilkstein, Martin J.

AU - Riscoe, Michael K.

AU - Kelly, Jane X.

PY - 2020/6/11

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N2 - The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

AB - The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

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KW - Humans

KW - Mice, Inbred C57BL

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KW - Half-Life

KW - Male

KW - Structure-Activity Relationship

KW - Cell Survival/drug effects

KW - Life Cycle Stages/drug effects

KW - Malaria/drug therapy

KW - Hep G2 Cells

KW - Plasmodium falciparum/drug effects

KW - Animals

KW - Female

KW - Mice

KW - Antimalarials/chemistry

KW - Disease Models, Animal

UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/31

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SP - 6179

EP - 6202

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.

Abstract

Funding

ASJC Scopus Subject Areas

Keywords

Disciplines

Access to Document

OpenUrl availability

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