Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases

Abstract

Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases.

Keywords: SLE; hydroxychloroquine; lysosomotropic actions; quinacrine; therapies; toxicity profiles.

Figure 1.

Historical developmental pathways of chloroquine analogues.

Figure 2.

Major inhibitory roles of chloroquine in lysosomes. Intralysosomal pH is increased by chloroquine. Note that the raised pH is not involved in the antimalarial mechanism of action.

Figure 3.

Major anti-inflammatory and immunomodulatory effects of chloroquine analogues.

Figure 4.

Mechanisms of anticancer actions of chloroquine analogues. (a) Radiosensitizing effect: membrane-damaging proteolytic enzymes are released and lysosomal permeability is increased as a result of radiation and the effect of chloroquine. (b) Chemosensitizing effect: anticancer drug extrusion is prevented via blockade of ABC transporters with chloroquine, and intracellular drug availability is increased and cells damaged.