Abstract
Leishmaniasis is a growing health problem worldwide. As there are certain drawbacks with the drugs currently used to treat human leishmaniasis and resistance to these drugs is emerging, there is a need to develop novel antileishmanial compounds, among which isoquinoline alkaloids are promising candidates. In this study, 18 novel oxoisoaporphine derivatives were synthesized and their possible antileishmanial activity was evaluated. The in vitro activity of these derivatives against Leishmania amazonensis axenic amastigotes was first evaluated, and the selected compounds were then tested in an inhibition assay with promastigotes of L. infantum, L. braziliensis, L. amazonensis and L. guyanensis, and with intracellular amastigotes of L. infantum and L. amazonensis. Finally, the most active compounds, OXO 1 (2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one) and OXO 13 (2,3,8,9,10,11-hexahydro-7H-dibenzo[de,h]quinolin-7-one), were tested in BALB/c mice infected with L. infantum. Treatment of mice at a dose of 10 mg/kg with OXO 1 yielded significant reductions (p<0.05) in parasite burden in liver and spleen (99% and 78%, respectively) whereas with OXO 13 were not significant. Although previous reports suggest that this family of molecules displays inhibitory activity against monoamine oxidase A and acetylcholinesterase, these enzymes were not confirmed as targets for antileishmanial activity on the basis of the present results. However, after development of a new bioinformatics model to analyze the Leishmania proteome, we were able to identify other putative targets for these molecules. The most promising candidates were four proteins: two putative pteridine reductase 2 (1MXF and 1MXH), one N-myristoyltransferase (2WUU) and one type I topoisomerase (2B9S).
Highlights
Leishmaniasis is a vector-borne disease caused by an obligate intra-macrophage protozoan parasite
The results showed that only OXO 1 and OXO 13 rendered maximal inhibition at the lowest concentration of 0.05 mg/ml (Table 1)
Compound OXO 13 was the most active (IC50 lower than that recorded for the reference compound, miltefosine), but this compound displayed a high degree of toxicity (CC50 = 31.4 mg/ml compared with 55.4 mg/ml for miltefosine)
Summary
Leishmaniasis is a vector-borne disease caused by an obligate intra-macrophage protozoan parasite. The disease, which is endemic in large areas of tropical and subtropical countries, is caused by more than 20 species of Leishmania and transmitted to humans by more than 30 different species of phlebotomine sandflies. The three major clinical syndromes that are recognized in human disease are visceral, cutaneous and muco-cutaneous leishmaniasis [1]. An estimated 2 million new cases (1.5 million cases of cutaneous leishmaniasis and 500,000 of visceral leishmaniasis) occur annually, and about 12 million people are currently infected [2]. This epidemiological scenario has worsened because dogs are the principal reservoirs as well as suffers of the disease, for which fully successful treatment is still lacking [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
