Investigating drug repositioning as a route to combat drug resistance in Plasmodium falciparum Malaria

Munir, Attika

Abstract

Malaria is known as one of the deadliest and life-threatening parasitic diseases. It is caused by a bite of an infected female Anopheles mosquito transmitting Plasmodium parasites to humans. In 2021, there was an estimated 247 million cases of malaria: with fatalities at 619,000. Although chemotherapy and vector control measures have been the mainstay of disease control, over time there has been an emergence of drug resistance to most of the antimalarial therapies available. There is an urgent need for novel therapeutic drugs to become available. Traditional drug development pipelines and research would have significant time and cost implications, whereas a more time-efficient drug discovery pathway such as drug repositioning could yield much needed results. Drug repositioning is a novel drug discovery pathway using drugs that are used for other conditions and repurposing them for another. In this study, six compounds were selected from the LOPAC FDA-approved (Food and Drug Administration agency) drug library to test for anti-malarial activity (Fluoxetine, Mitoxantrone, Nicardipine, Propafenone, Ivermectin and Nicardipine). Antimalarial activity was defined in the multi drug resistant Plasmodium falciparum strain K1 using the in vitro SYBR Green micro-titre drug assay. The IC50 values were as follows: Ivermectin 0.7067M, Mitoxantrone 1.636M, Fluoxetine 11.23M, Nicardipine 4.388M, Propafenone >200M and Spironolactone >200M using Chloroquine as a control. Cell cytotoxicity profiles were determined for the selected compound panel using MTT assays in human HepG2 cell lines. All compounds apart from Mitoxantrone showed better safety profiles than the control Cisplatin (IC50 0.665 µM). The calculated selectivity indices for the main two drug leads (Ivermectin SI 77.95 and Nicardipine SI 21.23) showed promising results for progression to second phase optimisation. The study provides preliminary data on a panel of compounds with antimalarial efficacy, which could be further explored through derivatisation or as combinatorial partner drugs.

Citation

Munir, A. (2024). Investigating drug repositioning as a route to combat drug resistance in Plasmodium falciparum Malaria. (Thesis). University of Salford

• Thesis Type: Thesis
• Deposit Date: Feb 23, 2024
• Publicly Available Date: Apr 27, 2024
• Award Date: Mar 26, 2024