Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs

Abstract

Cinnamic acids are compounds of natural origin that can be found in many different parts of a wide panoply of plants, where they play the most diverse biological roles, often in a conjugated form. For a long time, this has been driving Medicinal Chemists towards the investigation of the therapeutic potential of natural, semi-synthetic, or fully synthetic cinnamic acid conjugates. These efforts have been steadily disclosing promising drug leads, but a wide chemical space remains that deserves to be further explored. Amongst different reported approaches, the combination or conjugation of cinnamic acids with known drugs has been addressed in an attempt to produce either synergistic or multi-target action. In this connection, the present review will focus on efforts of the past decade regarding conjugation with cinnamic acids as a tool for the rescuing or the repurposing of classical antimalarial drugs, and also on future perspectives in this particular field of research.

Keywords: amide; aminoquinoline; antimalarial; antioxidant; antiparasitic; antiproliferative; artemisinin; chloroquine; cinnamic; ionic liquid; primaquine; repurposing; rescuing.

Figure 1

General structure of cinnamic acids (1) and structures of the antimalarial drugs chloroquine (2), primaquine (3), mepacrine (4), and artemisinin (5).

Figure 2

Chloroquine-cinnamic acid conjugates developed by Pérez et al. [53,54,55,59].

Figure 3

Primaquine-cinnamic acid conjugates proposed by Pérez et al. [61].

Figure 4

Primaquine and chloroquine fumardiamides reported by Zorc and co-workers [62].

Figure 5

9-aminoacridine-cinnamic acid conjugates developed by Gomes and co-workers [64,65].

Figure 6

Antimalarial-cinnamic acid conjugates and analogues reported by Wiesner et al. [29,67,68].

Figure 7

Antiproliferative primaquine-CA conjugates developed by Zorc et al. [74,75].

Figure 8

Antiproliferative dihydroartemisinin-CA conjugates developed by Xu et al. [78].

Figure 9

Antimalarial drug-cinnamic acid ionic liquids developed by Ferraz et al. [85,92,93,94].

Figure 10

(A) Representative bright field images (Leica DMI6000 microscope, scale bar 30 μm) of BALB/c mice bone marrow-derived macrophages (BMM) incubated with either a covalent chloroquine-CA conjugate 8 (n = 4, R = p-Me)—left, or its surrogate ionic liquid 20—right, at 100 μM (upper panel) or at 12.5 (8) and 18.75 (20) μM (lower panel). (B) Cytotoxicity for BMM was determined in parallel by the resazurin reduction assay (average ± SD) in three independent experiments. The abrupt decrease in macrophage viability above 12.5 μM is probably related to the crystallization of the compound observed for 8, and not for 20 [97].