Lead Optimization of Second-Generation Acridones As Broad-Spectrum Antimalarials

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2020 May 12

PMID 32390431

Citations 6

Authors

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

Affiliations

Soon will be listed here.

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.

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