Synthesis of limonene β-amino alcohol derivatives in support of new antileishmanial therapies

Abstract

A series of seven limonene β-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene β-amino alcohol derivatives.Key words: limonene -β-amino alcohol -synthesis -leishmaniasis -Leishmania braziliensis -neglected diseases Parasitic diseases are the cause of much suffering and death throughout the world, mainly in underdeveloped areas like Africa, Asia and Latin America. In these regions, the economic and social impacts caused by these sicknesses are very high because the parasites infect millions of people. Among these parasites, the Protozoa genera are responsible for the principal sicknesses, and leishmaniasis is one of the strictest parasitic diseases caused by multiple species of Leishmania (WHO 2008). The disease is endemic in tropical regions, affecting over 12 million people in 88 countries and its clinical manifestations can occur in cutaneous, mucocutaneous and visceral forms (Croft & Yeardley 2002, Murray et al. 2005. The main health organisations are concerned about these statistics due to the significant number of cases (Nwaka & Hudson 2006). Despite this, the therapies currently available to treat this illness are deficient and outdated and most present several sideeffects. Moreover, the widespread development of resistance by certain strains of leishmaniasis to antimonial compounds contributes to poor health conditions in underdeveloped countries. Chemotherapy of leishmaniasis (Croft & Yeardley 2002, Nwaka & Hudson 2006 consists of using intravenous drugs like antimonial compounds as first-choice drugs and amphotericine B as second-choice. In countries where many resistance cases to the antimonial drugs are reported, this antibiotic is used as a first-choice. Intramuscular Pentamidine is administrated in patients infected with Leishmania panamensis and Leishmania braziliensis. Miltefosine and fluconazole are currently the only effective oral treatments for leishmaniasis. However, all of these treatments have significant drawbacks in terms of route of administration, length of treatment (21-28 days), toxicity and cost, which limit their use in endemic areas (Croft & Yeardley 2002, DNDI 2003, Murray et al. 2005. These arguments by themselves justify the search for new leishmanicidal drugs, which makes the search for new agents a priority for its erradication. In this context, the strategy of following new leads to treat neglected diseases starting from natural sources is widely used by medicinal chemists (Viegas et al. 2006, Newman & Cragg 2007.Limonene is a main constituent of essential oils of citrus plants, is abundant in nature and is available in both enantiomeri...

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Valorization of Biomass Derived Terpene Compounds by Catalytic Amination

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