Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study

Leishmaniasis, which is manifested in different clinical forms, is a vector-borne disease caused by protozoan parasites belonging to the genus Leishmania.¹ Although a majority of literature mentions only one genus (Lutzomyia) transmitting leishmaniasis to humans in the USA, elsewhere in the world the genus Phlebotomus is considered to be the vector of leishmaniasis.² Female sand flies act as carriers of the parasite, and the parasite is transmitted from person to person or from a range of animals to humans.¹ In fact, Leishmania species are widespread in 88 countries, affecting the visceral organs, skin and mucous membrane.³

Treatment options for leishmaniasis are very limited. Although studies have identified several antigens, as potential vaccine target, currently no vaccine against the disease is in routine use or in advanced stage of development.⁴ There are two common therapies under use, which contain pentavalent antimony. It is not completely understood how these drugs act against the parasite. These drugs induce severe adverse effects such as myalgia, anorexia, nausea, vomiting, lack of appetite, tremor, diarrhea, and fever.⁵ In many parts of the world, the parasite has become resistant to antimony when used in treating visceral or mucocutaneous leishmaniasis.⁶ Very few new drugs have been discovered⁷ such as miltefosine, used for treatment of visceral and cutaneous leishmaniasis in different countries. This drug also has unwanted side effects, mainly gastrointestinal disturbance.⁸ In addition, there are problems associated with the use of miltefosine, being teratogenic and has unfavorable pharmacokinetic properties.⁶ The Institute for One World Health has reintroduced the drug paromomycin for treatment of leishmaniasis, on the basis of results which led to its approval as an orphan drug. A 21-day study using paromomycin produced a definitive cure in >90% patients with visceral leishmaniasis.⁹ Drug-resistant leishmaniasis may respond to immunotherapy (inoculation with parasite antigens plus an adjuvant), which aims to stimulate the body’s own immune system to kill the parasite. However, the cost for this kind of treatment is prohibitive.¹⁰

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