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; Brett R. Bayles; Roland A. Cooper; Kevin A. Reynolds; Martin J. Smilkstein; Michael K. Riscoe; Michael K. Riscoe; Jane X. Kelly; Jane X. Kelly

doi:10.1021/acs.jmedchem.0c00539

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, Brett R. Bayles, Roland A. Cooper, Kevin A. Reynolds, Martin J. Smilkstein, Michael K. Riscoe, Michael K. Riscoe, Jane X. Kelly, Jane X. Kelly

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

8 Scopus citations

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	English (US)
Pages (from-to)	6179-6202
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.0c00539
State	Published - Jun 11 2020
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/acs.jmedchem.0c00539

Cite this

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://doi.org/10.1021/acs.jmedchem.0c00539

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, 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, Ceja, FG, Rasmussen, SA, Tumwebaze, PK, Rosenthal, PJ, Mu, J, Bayles, BR, Bayles, BR, Cooper, RA, Reynolds, KA, Smilkstein, MJ, Riscoe, MK, Riscoe, MK, Kelly, JX & 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://doi.org/10.1021/acs.jmedchem.0c00539

@article{73093912bfa142efa6d767c29f55888b,

title = "Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = jun,

day = "11",

doi = "10.1021/acs.jmedchem.0c00539",

language = "English (US)",

volume = "63",

pages = "6179--6202",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "11",

}

TY - JOUR

T1 - Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

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

Y1 - 2020/6/11

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.

UR - http://www.scopus.com/inward/record.url?scp=85086345898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85086345898&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.0c00539

DO - 10.1021/acs.jmedchem.0c00539

M3 - Article

C2 - 32390431

AN - SCOPUS:85086345898

SN - 0022-2623

VL - 63

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

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this