Quinine and chloroquine: Potential preclinical candidates for the treatment of tegumentary Leishmaniasis.

Leishmaniasis is an endemic disease in more than 90 countries, constituting a relevant public health problem. Limited treatment options, increase in resistance, and therapeutic failure are important aspects for the discovery of new treatment options. Drug repurposing may accelerate the discovery of antiLeishmanial drugs. Recent tests indicating the in vitro potential of antimalarials Leishmania resulted in the design of this study. This study aimed at evaluating the susceptibility of Leishmania (L.) amazonensis to chloroquine (CQ) and quinine (QN), alone or in combination with amphotericin B (AFT) and pentamidine (PTN). In the in vitro tests, first, we evaluated the growth inhibition of 50 % of promastigotes (IC50) and cytotoxicity for HepG2 and THP-1 cells (CC50). The IC50 values of AFT and PNT were below 1 µM, while the IC50 values of CQ and QN ranged between 4 and 13 µM. Concerning cytotoxicity, CC50 values ranged between 7 and 30 µM for AFT and PNT, and between 22 and 157 µM for the antimalarials. We also calculated the Selectivity Index (SI), where AFT and PTN obtained the highest values, while the antimalarias obtained values between 5 and 12. Both antimalarials were additive (Æ©FIC 1.05-1.8) in combination with AFT and PTN. For anti-amastigote activity, the drugs obtained the following ICA50 values: AFT (0.26 µM), PNT (2.09 µM), CQ (3.77 µM) and QN (24.5 µM). In the in vivo tests, we observed that the effective dose for the death of 50 % of parasites (ED50) of AFT and CQ were 0.63 mg/kg and 27.29 mg/kg, respectively. When combining CQ with AFT, a decrease in parasitemia was observed, being statistically equal to the naive group. For cytokine quantification, it was observed that CQ, despite presenting anti-inflammatory activity was effective at increasing the production of IFN-γ. Overall, our data indicate that chloroquine will probably be a candidate for repurposing and use in drug combination therapy.

In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs.

Malaria, caused by protozoa of the genus Plasmodium, is a disease that infects hundreds of millions of people annually, causing an enormous social burden in many developing countries. Since current antimalarial drugs are starting to face resistance by the parasite, the development of new therapeutic options has been prompted. The enzyme Plasmodium falciparum enoyl-ACP reductase (PfENR) has a determinant role in the fatty acid biosynthesis of this parasite and is absent in humans, making it an ideal target for new antimalarial drugs. In this sense, the present study aimed at evaluating the in silico binding affinity of natural and synthetic amides through molecular docking, in addition to their in vitro activity against P. falciparum by means of the SYBR Green Fluorescence Assay. The in vitro results revealed that the natural amide piplartine (1a) presented partial antiplasmodial activity (20.54 µM), whereas its synthetic derivatives (1m-IC50 104.45 µM), (1b, 1g, 1k, and 14f) and the natural amide piperine (18a) were shown to be inactive (IC50 > 200 µM). The in silico physicochemical analyses demonstrated that compounds 1m and 14f violated the Lipinski's rule of five. The in silico analyses showed that 14f presented the best binding affinity (- 13.047 kcal/mol) to PfENR and was also superior to the reference inhibitor triclosan (- 7.806 kcal/mol). In conclusion, we found that the structural modifications in 1a caused a significant decrease in antiplasmodial activity. Therefore, new modifications are encouraged in order to improve the activity observed.

Correction to: In silico evaluation and in vitro growth inhibition of Plasmodium falciparum by natural amides and synthetic analogs.

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