Evolution of Acridines and Xanthenes as a Core Structure for the Development of Antileishmanial Agents

Carlos F M Silva,Artur M S Silva,Diana C G A Pinto,Pedro A Fernandes

doi:10.3390/ph15020148

Carlos F M Silva, Artur M S Silva + Show 2 more

Open Access

https://doi.org/10.3390/ph15020148

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Abstract

Nowadays, leishmaniasis constitutes a public health issue in more than 88 countries, affecting mainly people from the tropics, subtropics, and the Mediterranean area. Every year, the prevalence of this infectious disease increases, with the appearance of 1.5–2 million new cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis, endangering approximately 350 million people worldwide. Therefore, the absence of a vaccine or effective treatment makes the discovery and development of new antileishmanial therapies one of the focuses for the scientific community that, in association with WHO, hopes to eradicate this disease shortly. This paper is intended to highlight the relevance of nitrogen- and oxygen-containing tricyclic heterocycles, particularly acridine and xanthene derivatives, for the development of treatments against leishmaniasis. Thus, in this review, a thorough compilation of the most promising antileishmanial acridine and xanthene derivatives is performed from both natural and synthetic origins. Additionally, some structure–activity relationship studies are also depicted and discussed to provide insight into the optimal structural features responsible for these compounds’ antileishmanial activity.

Highlights

Leishmaniasis is amongst the most neglected diseases in modern times, affecting mainly people from developing countries of the tropics, subtropics, and the Mediterranean basin
The results of this study demonstrated that the mono-substituted acridines present stronger antileishmanial activities than their disubstituted homologs, with the latter group being weakly active against the promastigote form of the parasite
Leishmania, with the use of organoantimonial compounds remaining as the first line of treatment against all forms of leishmaniasis

Summary

Introduction

Leishmaniasis is amongst the most neglected diseases in modern times, affecting mainly people from developing countries of the tropics, subtropics, and the Mediterranean basin. 350 million people are considered at risk of developing this disease [1] This disease constitutes a public health issue in more than 88 countries, with an estimated world prevalence of 12 million cases covering all forms of leishmaniasis [2]. These numbers tend to increase, since 1.5–2 million new cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis appear each year, with a mortality rate of approximately 50,000 deaths annually. The need for safer and more effective medicines to treat leishmaniasis drove the search for new compounds, with amphotericin B (AmB) 4 (Figure 1) emerging as the first alternative to the usual pentavalent antimonials [1,8]. This paper intends to compile and emphasize the potential of two major classes of compounds, namely acridines and xanthenes, to develop novel treatments against leishmaniasis, and highlight a neglected disease and encourage the scientific community to devote more efforts to finding efficient treatment

Acridines

Xanthenes

Findings

Conclusions and Future Perspectives