Chang, Sandra PhD

Research Overview

2010-2011 RMATRIX Collaboration Pilot Projects Program Awards

(Co-funded in Partnership with the RTRN Small Grant Awards Program)

Project Description

Abstract

Design of imido-substituted 2-chloro-1, 4-naphthoquionones as anti-malarial drugs

The morbidity and mortality associated with Plasmodium falciparum (P. falciparum) malaria have spurred efforts to find novel antimalarial agents with improved potency and selectivity. Leads for agents continue to be obtained naturally (plants and microorganisms) or by chemical synthesis. The structural diversity of compounds with good micromolar and lower activity point to the tolerance for different structural elements in the antimalarial pharmacophore. This may also be a reflection of the varied targets present in the plasmodia. The challenge in malaria chemotherapy is to find safe and selective agents whose potencies will not be compromised by plasmodial resistance. Modification of potential leads should also aim at improving drug-like character, viz. to ensure acceptable oral bioavailability. The 1 ,4-naphthoquinone scaffold has received attention as a pharmacophore for the design of antitumor and antimalaria agents. We have shown that some imido-substituted 2-chloro-1 ,4-naphthoquinones (IMIDOs) were selective inhibitors of the mitogen-activated protein kinase kinase 1 (MEK1). Acyclic imido derivatives have antitumor activity against prostate cancer cell lines, and some cyclic ones were more selective for MEK1 with reduced cytotoxicity. Our long-term goal is to design and develop compounds that are safe, effective, affordable, and capable of reversing plasmodial resistance. This proposal will focus on developing IMIDOs as a novel class of anti-malarial agents guided by these Specific Aims. 1. Synthesize IMIDOs with cyclic/ acyclic groups on the imide moiety for antimalaria screening. 2. Evaluate in vitro antimalaria profile of new analogs in chloroquine-sensitive (3D7and W2) and resistant (D6 and 7G8) strains of P. falciparum using Malaria SYBR Green I-based Fluorescent (MSF) assay to quantify parasite growth inhibition and the 50% inhibitory concentration (IC50) in parasitized red cells. 3. Identify metabolic pathways of P. falciparum affected by treatment with IMIDOs, and compare untreated cultures with those treated in lead IMIDOs by ESI(+/-) Quadrupole Time-of-Flight (QITOF) mass spectrometry using a targeted metabolomics approach to determine differences in metabolite abundance patterns between these cultures. Data from these studies will facilitate the application for external funding. RELEVANCE: As parasitic resistance increases, new drugs for treating P. falciparum malaria, the world’s most deadly disease, are urgently needed. 350-500 million people/year are afflicted resulting in 1-2 million deaths annually, most deaths involving children and pregnant women in sub-Saharan Africa, the Americas and Asia. This project proposes to develop IMIDOs as novel drugs and define parasite metabolic pathways affected by these drugs.