Joanna Wawszczyk, Radosław Wolan, Małgorzata Kapral

A new perspective on 4-aminoquinoline antimalarial drugs

2026-08-13

Subject of study. This study focuses on antimalarial drugs belonging to the 4-aminoquinoline derivative group: chloroquine and hydroxychloroquine. These compounds exhibit complex, multifactorial, and pleiotropic biological activities that extend substantially beyond their original antimalarial use. Currently, both drugs are the subject of intensive investigation regarding their potential for therapeutic repositioning in novel domains of contemporary pharmacotherapy.

Research objective. The goal of this study is to comprehensively characterize  the current clinical applications of chloroquine and hydroxychloroquine and to evaluate  their potential for repositioning beyond established indications. This work aims to provide a detailed synthesis of the newly elucidated mechanisms of action of these drugs that may account for the broad spectrum of biological effects. An additional aim is to critically appraise  the clinical efficacy and safety profiles of both drugs, thereby enabling the identification of new research challenges.

Literature search and selection methodology. The methodological basis of the presented research was the systematic selection and critical analysis of recent scientific literature. Data were primarily obtained from electronic databases (PubMed, Google Scholar, Scopus). Publications in Polish and English were selected, including original articles, reviews, clinical trials, and meta-analyses. This approach enabled an assessment of therapeutic efficacy, drug–drug interactions, and toxicity profiles. The main keywords used in the literature search were: „chloroquine”, „hydroxychloroquine”, „immunology”, „autophagy”, „cancer”, and „repurposing”.

Results. Chloroquine and hydroxychloroquine accumulate in acidic intracellular organelles, leading to an increase in their intraluminal pH and functional alterations. These effects result in inhibition of autophagic flux and attenuation of excessive inflammatory responses, including the modulation of TLR-dependent signaling pathways. These properties underlie their established use not only in malaria, but also in the management of autoimmune disorders. Numerous reports also suggest antiviral activity of these drugs; however, such effects have not been confirmed in randomized clinical trials. The literature further indicates a potential for repositioning in oncology, particularly with regard to their putative anticancer activity when employed as adjuvant agents that sensitize tumor cells to conventional cytotoxic chemotherapy and targeted therapies. Nonetheless, when exploring novel therapeutic applications of these compounds, their adverse effect profiles must be considered.

Conclusions. Both chloroquine and hydroxychloroquine demonstrate pleiotropic potential that extends beyond their traditional indications, particularly offering the prospect of effective use in adjuvant anticancer therapies. Key factors limiting their clinical use, particularly in oncology, include nonspecific tissue distribution, difficulties in achieving desired concentrations in the tumor microenvironment, and the risk of toxicity, particularly cardiotoxicity and ocular toxicity.

Future therapeutic strategies should prioritize optimization of the benefit–risk ratio through toxicity reduction and enhancement of efficacy, as well as the development of novel formulations and delivery systems enabling targeted transport of the active substances with minimized systemic exposure.

Keywords: cancer, autoimmune diseases, chloroquine, hydroxychloroquine, repositioning, pterostilbene.

© Farm Pol, 2026, 82(2): 85–98