Bioassay-directed fractionation of extracts from the fermentation broth and mycelium of the fungus Edenia sp. led to the isolation of five antileishmanial compounds, preussomerin EG1 (1), palmarumycin CP 2 (2), palmarumycin CP 17 (3), palmarumycin CP 18 (4), and CJ-12,371 (5). Compounds 3 and 4 are new natural products, and this is only the second report of compound 1. The structures of compounds 1−5 were established by spectroscopic analyses (HRMS and NMR). All metabolites caused significant inhibition of the growth of Leishmania donovani in the amastigote form, with IC 50 values of 0.12, 3.93, 1.34, 0.62 and 8.40 μM, respectively. Compounds 1−5 were inactive when tested against Plasmodium falciparum or Trypanasoma cruzi at a concentration of 10 μg/mL, indicating that they have selective activity against Leishmania parasites. Compounds 1−5 showed weak cytotoxicity to Vero cells (IC 50 of 9, 162, 174, 152 and 150 μM, respectively), however, the therapeutic window of these compounds is quite significant with 75, 41, 130, 245 and 18 times (respectively) more anti-leishmanial activity than cytotoxicity.Leishmaniasis is a major tropical disease which largely affects populations those of the developing world. According to the World Health Organization (WHO), leishmaniasis can be classified into four main forms: visceral leishmaniasis (the most dangerous because it can be mortal), cutaneous leishmaniasis (the most common form, which causes a variety of skin lesions), mucocutaneous leishmaniasis (which begins with skin ulcers that can spread, causing tissue destruction, mainly of the nose and mouth), and diffuse cutaneous leishmaniasis (produces chronic skin lesions which are very difficult to cure). 1 Current treatment against leishmaniasis is based on toxic chemotherapeutic compounds, such as sodium stibogluconate and meglumine antimonate, that have several serious side effects which themselves can be fatal to patients. 1,2 Moreover, these agents are expensive and therapies are required for relatively long durations, two characteristics which combine to exclude many patients from having access to any treatment. 1,2 While approximately 600,000 infections are officially reported each year, *Author to whom correspondence should be addressed. (Table 1), interpreted from multiplicity-edited HSQC data as 10 quaternary, two methylene, and eight methine carbons. This spectrum also had resonances for a cyclic ketone (δ C 202.0, C-4) and a naphthalene ring system [δ C 146.3 (C-1'); 110.5 (C-2'); 127.6 (C-3'); 121.9 (C-4'); 134.1 (C-4a'); 121.9 (C-5'); 127.6 (C-6'); 110.5 (C-7'); 146.3 (C-8'); 113.5 (C-8a')]. HMBC correlations supported these assignments as did data comparisons with known compounds 2 and 5. The chemical shift of the two-carbon resonance at δ C 146.3 was consistent with the placement of a dioxin bridge to C-1' and C-8' of the naphthalene core. Finally, the chemical shifts of the signals at δ C 157.2 and 147.6 were consistent with the positioning of phenolic hydroxy groups at C-5 and C-8. HMBC correlati...
Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A–C (1–3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.
Tropical parasitic and infectious diseases, such as leishmaniasis, pose enormous global health threats, but are largely neglected in commercial drug discovery programs. However, the Panama International Cooperative Biodiversity Group (ICBG) has been working to identify novel treatments for malaria, Chagas' disease, and leishmaniasis through an investigation of plants and microorganisms from Panama. We have pursued activity-guided isolation from an extract of Lyngbya majuscula that was found to be active against leishmaniasis. A new modified linear peptide from the dragonamide series was isolated, dragonamide E (1), along with two known modified linear peptides, dragonamide A (2) and herbamide B (3). Dragonamides A and E, and herbamide B, exhibited antileishmanial activity with IC 50 values of 6.5, 5.1, and 5.9 µM, respectively. Spectroscopic and stereochemical data for dragonamide E (1) and herbamide B (3; the spectroscopic and stereochemical data for this substance is incomplete in the literature) are presented as well as comparisons of biological activity within the dragonamide compound family. Biosynthetic differences among marine compounds with a terminal free amide are also discussed.Tropical diseases such as leishmaniasis, malaria, and Chagas'disease affect millions of people in equatorial countries each year.1 Inhabitants of these developing-world tropical countries are both at high risk from infection and are often those with the least socio-economic ability to obtain proper treatments; therefore, they are the most likely to develop serious and often fatal illnesses.2 Many tropical diseases have developed resistance to existing therapeutics, thus limiting the effectiveness of these treatments. A majority of the existing agents for treating tropical diseases also have serious side effects that reduce patient compliance with treatment regimens, or in some cases, prohibit any treatment at all. 1 Tropical diseases are largely overlooked in drug discovery programs by major pharmaceutical companies due to the lack of significant financial return on this expensive and time-consuming process (only 13 of the 1,300 *To whom correspondence should be addressed. Tel: +1-858-534-0578. Fax: +1-858-534-0529. wgerwick@ucsd.edu. ║ Current address: Department of Chemistry and Biochemistry, University of California, Santa Cruz. Supporting Information Available: Results and DiscussionL. majuscula was collected using snorkeling in shallow waters from Bocas del Toro, Panama in 2006, and subsequently extracted and fractionated using normal-phase flash chromatography. One of the fractions (60% EtOAc/hexanes) exhibited strong anti-leishmanial activity (7.2% of control parasite growth at 10 µg/mL, experimental detail in Supporting Information) while a second more polar fraction eluting with 100% EtOAc exhibited less potent anti-leishmanial activity (38.2% of control parasite growth at 10 µg/mL). This more polar (100% EtOAc) fraction was successively purified by RP-SPE column chromatography and RP-HPLC, and two compounds w...
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