N -Cinnamoylated Aminoquinolines as Promising Antileishmanial Agents

Abstract

A series of cinnamic acid conjugates of primaquine and chloroquine were evaluated for their in vitro antileishmanial activities. Although primaquine derivatives had modest activity, chloroquine conjugates exhibited potent activity against both promastigotes (50% inhibitory concentration [IC 50 ] ‫؍‬ 2.6 to 21.8 M) and intramacrophagic amastigotes (IC 50 ‫؍‬ 1.2 to 9.3 M) of Leishmania infantum. Both the high activity of these chloroquine analogues and their mild-to-low toxicity toward host cells make them promising leads for the discovery of new antileishmanial agents. Leishmania parasites maintain their life cycle by alternating between promastigotes in the gut of phlebotomine insects and amastigotes inside macrophages of mammalian hosts (1, 2). These protozoa cause leishmaniasis, a complex of mammalian diseases whose clinical symptoms range from self-healing cutaneous lesions to the more severe visceralizing infection (3). Human visceral leishmaniasis (VL) results from infection with L. donovani and L. infantum and is usually fatal if left untreated, accounting for more than 50,000 deaths per year (4, 5). The management of VL relies mainly on chemotherapy with pentavalent antimonials, pentamidine, paromomycin, amphotericin B or its lipid formulations, and miltefosine (5, 6). However, the treatment of this disease is hindered by the limited efficacy, high toxicity, reduced bioavailability, high cost, and parasite resistance to the action of several of the available drugs (7). As such, it is mandatory to develop novel compounds devoid of these limitations. To respond to those needs, we have tested the activity of cinnamic acid conjugates of the 8-aminoquinoline primaquine (PQ) and the 4-aminoquinoline chloroquine (CQ) against L. infantum. The rationale for these tests was that (i) these conjugates have been recently reported as interesting antimalarial leads (8-10) and (ii) PQ (compound 1) and CQ (compound 3) have proven activity against several protozoans, including visceralizing Leishmania (11-15).All the N-cinnamoylated aminoquinolines (compounds 2a to 2k and 5a to 5j) and compound 3b (CQ-C4 [see Table 2]; used as the parent compound for the synthesis of 5a to 5j) were synthesized as previously described (8, 10). Cinnamic acid (compound 4), PQ, CQ (Sigma-Aldrich, Spain), and miltefosine (Cayman Chemicals) were commercially acquired. All test compounds and the reference drugs PQ and miltefosine were dissolved in dimethyl sulfoxide (Sigma), while CQ (sodium salt; Sigma) was dissolved in phosphate-buffered saline (PBS). All solutions were stored at Ϫ20°C until use. Their antileishmanial activity was initially evaluated on the promastigote stage of L. infantum (MHOM/MA/67/ ITMAP-263, zymodeme MON-1; laboratory reference strain [16]). Briefly, promastigotes (1 ϫ 10 6 /well) were cultured at 25°C in complete RPMI medium (Gibco, Life Technologies) (13) supplemented with the different compounds at concentrations between 0.63 and 80 M. The antileishmanial activity was assessed at 72 h of culture by the resazurin meth...

Antileishmanial Activity, Cytotoxicity and Mechanism of Action of Clioquinol Against Leishmania infantum and Leishmania amazonensis Species

“…The pharmacological properties of the quinoline ring illustrate the number of commercial products containing this heterocyclic system . Quinoline‐based compounds present a variety of biological actions, such as antimalarial and antileishmanial agents . As a consequence, this study illustrates the leishmanicidal activity of 8‐HQN, a quinoline derivate, against distinct Leishmania species .…”

Insights into the structural patterns of the antileishmanial activity of bi- and tricyclic N-heterocycles

“…The selectivity index of this chloroquine analogue was 3 to 4 times higher (8.5/13.1 L. major/L. panamensis ) than the SI of chloroquine (3.1) previously reported under similar experimental conditions 33 Since chloroquine is an approved drug, these SI values suggest that compound 12 is a promising candidate for further therapeutic investigation.…”

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

“…Remarkably, despite antileishmanial activity being more often associated to 8-aminoquinolines, like sitamaquine [82] or tafenoquine [83], conjugates 8, which embed a 4-aminoquinoline moiety, were significantly more active in vitro than the primaquine-derived conjugates 9 against promastigotes (3.1 < IC 50 < 21 µM for compounds 8 versus 16 < IC 50 < 53 µM for compounds 9) of L. infantum. Moreover, compounds 8 were comparable (1.2 < IC 50 < 9.3 µM) to the reference antileishmanial drug miltefosine (IC 50 = 4.1 µM) against intracellular amastigotes, while having low-to-mild toxicity against the mouse bone marrow-derived macrophages [81]. The authors further found that the effect of group R on the activity in the best performing series of compounds 8 (n = 4) was not considerable.…”

“…Based on reported potent antimalarial activity of aminoquinoline-CA conjugates 8 ( Figure 2) and 9 (Figure 3), Vale-Costa et al tested these compounds against Leishmania infantum parasites [81]. Remarkably, despite antileishmanial activity being more often associated to 8-aminoquinolines, like sitamaquine [82] or tafenoquine [83], conjugates 8, which embed a 4-aminoquinoline moiety, were significantly more active in vitro than the primaquine-derived conjugates 9 against promastigotes (3.1 < IC 50 < 21 µM for compounds 8 versus 16 < IC 50 < 53 µM for compounds 9) of L. infantum.…”