A chloroquinoline derivate presents effective in vitro and in vivo antileishmanial activity against Leishmania species that cause tegumentary and visceral leishmaniasis
Graphical abstract
Introduction
Leishmaniases are diseases caused by protozoan parasites of the Leishmania genus, which present an annual estimated incidence of 1.5 to 2.0 million new cases, which range between 1.0 and 1.5 million cases of tegumentary leishmaniasis (TL), coupled with approximately 0.5 million new cases of visceral leishmaniasis (VL). Epidemiological data have proven that this disease complex is endemic in 98 countries, mainly in subtropical and tropical regions in the world [1,2]. TL can lead to self-healing cutaneous lesions, even causing mutilation and morbidity in patients. The disease is usually caused by Leishmania braziliensis, L. amazonensis, L. guyanensis, L. mexicana, and L. lainsoni species in the Americas, whereas VL, which is considered a fatal disease if acute and left untreated, can be caused by L. donovani and L. infantum species [3,4].
Treatment against leishmaniasis has been based on the use of pentavalent antimonials, although other drugs, such as free and liposomal amphotericin B (AmpB), miltefosine, paramomycin, and pentamidine have been also used [5]. However, problems related to their toxicity, high cost, and/or development of resistant strains have limited the efficacy of these therapeutics [6,7]. The prolonged administration of these compounds can cause adverse effects, such as renal, hepatic, and cardiac toxicity. These can also show variable efficacy according to the parasite strain, immune status of the hosts, and the emergence of drug resistance, all of which have been observed in the subcontinent of India and other regions [8,9]. Consequently, since the search to identify new antileishmanial targets is hampered due to the high investment necessary to develop new products, as well as by the lack of a profitable drug market [10], alternative means through which to identify new antileishmanial agents, such as plant derivates or synthetic products, could help to solve this relevant problem and make it possible to identify new therapeutics to be applied against leishmaniasis [11,12].
The interest in natural and/or synthetic molecules has increased in recent decades, and new agents have been evaluated in experimental trials [[13], [14], [15], [16]], although most have been tested in in vitro studies, and few in vivo treatment experiments have been developed using mammalian models [[17], [18], [19]]. Distinct molecule classes, such as flavonoids, terpenoids, quinolines, among others, have shown variable degrees of antileishmanial activity [[20], [21], [22], [23]]. In this aspect, quinoline derivatives have been applied as an important drug class, showing potent antitumoral, antiprotozoal, antimicrobial, and anti-inflammatory activity, among others, and did not cause significant toxicity in the hosts [[24], [25], [26], [27]].
Research groups have demonstrated the selective antileishmanial activity of the quinoline-based compounds against Leishmania models [[28], [29], [30]]. One of these molecules, clioquinol (5-chloro-7-iodoquinolin-8-ol), demonstrated high efficacy against L. amazonensis and L. infantum promastigotes and amastigotes, without causing toxicity in murine macrophages. It was also effective in the treatment of infected macrophages and in the inhibition of the infection of these cells using pre-treated parasites [31]. In another study, clioquinol was incorporated to a Poloxamer 407-based delivery system, and the formulation proved to be effective in the treatment of L. amazonensis-infected BALB/c mice [32].
In this context, in the present study, a new chloroquinoline derivate, AM1009 [N1-(7-chloroquinolin-4-yl)-N3-cyclohexylpropane-1,3-diamine], was in vitro tested against two Leishmania species that cause VL and TL around the world. The 50% Leishmania inhibitory concentration (EC50) and the 50% macrophage inhibitory concentration (CC50) in murine macrophages and in human red blood cells (RBC50) were investigated. Additionally, the treatment of infected macrophages and the inhibition of infection using pre-treated parasites were also evaluated, as were the mechanism of action in L. amazonensis and the in vivo therapeutic efficacy in treating Leishmania-chronically infected BALB/c mice. As a molecule control, clioquinol was used in the in vitro and in vivo experiments, as was AmpB, which was used as a drug control. Our purpose is to identify new candidates to be tested in future studies for treatment against leishmaniasis, which can present higher activity and selectivity when compared to previously described antileishmanial agents.
Section snippets
Synthesis of AM1009
To perform the synthesis of AM1009, 220 mg (0.668 mmol) N-(3-bromopropyl)-7-chloroquinolin-4-amine was added to a round bottom flask containing 464 mg (4.68 mmol) of cyclohexanamine, 462 mg (3.34 mmol) of potassium carbonate, and 1 mL of dimethylformamide PA. The flask was shaken for 20 h at 120 °C, and the reaction was completed by thin layer chromatography. After, the compound was mixed using distilled water and dichloromethane PA, and AM1009 was purified through a filtration using silica,
Antileishmanial activity, cytotoxicity, and selectivity index
The in vitro antileishmanial activity of AM1009 was evaluated against L. amazonensis and L. infantum promastigotes and axenic amastigotes. As molecule and drug control, clioquinol and AmpB were used, respectively. The EC50 values for AM1009, clioquinol, and AmpB against L. amazonensis promastigotes were 2.41 ± 0.28, 7.90 ± 0.65, and 0.13 ± 0.04 μM, respectively, and of 1.03 ± 0.22, 2.27 ± 0.44, and 0.34 ± 0.11 μM against the axenic amastigotes, respectively. Regarding the L. infantum species,
Discussion
Advances in the biochemical research applied in in vitro and/or in vivo parasitological and immunological studies to kill Leishmania parasites have been developed in order to identify new and non-toxic and cost-effective antileishmanial products to control this neglected disease in the world [38]. However, current therapeutics present problems, such as side effects, including arthralgia, myalgia, fever, weakness, besides renal, hepatic and cardiac toxicity, together with high cost and/or poor
Declaration of Competing Interest
The authors confirm that they have no conflicts of interest in relation to this work.
Acknowledgments
The authors would like thank to CAPES, CNPq, and FAPEMIG for the scholarships. This work was supported by grants from CNPq (APQ-408408/2016-2 and APQ-408675/2018-7).
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These authors contributed equally to this work.