Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis

Abstract

This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. Azasterols are a known class of (S)-adenosyl-L-methionine: ⌬ 24 -sterol methyltransferase(24-SMT) inhibitors in fungi, plants, and some parasitic protozoa. The compounds prepared showed activity at micromolar and nanomolar concentrations when tested against Leishmania spp. and Trypanosoma spp. The enzymatic and sterol composition studies indicated that the most active compounds acted by inhibiting 24-SMT. The role of the free hydroxyl group at position 3 of the sterol nucleus was also probed. When an acetate was attached to the 3␤-OH, the compounds did not inhibit the enzyme but had an effect on parasite growth and the levels of sterols in the parasite, suggesting that the acetate group was removed in the organism. Thus, an acetate group on the 3␤-OH may have application as a prodrug. However, there may be an additional mode(s) of action for these acetate derivatives. These compounds were shown to have ultrastructural effects on Leishmania amazonensis promastigote membranes, including the plasma membrane, the mitochondrial membrane, and the endoplasmic reticulum. The compounds were also found to be active against the bloodstream form (trypomastigotes) of Trypanosoma brucei rhodesiense, a causative agent of African trypanosomiasis.

Dynamics of sterol synthesis during development of Leishmania spp. parasites to their virulent form

“…In one study, cholesterol and cholesta-5,7,24-trien-3β-ol were 2× and 32× higher, respectively, whereas ergosta-7,24(28)-dien-3β-ol and ergosta-5,7,24(28)-trien-3β-ol were 15× and 5 × lower, respectively, in miltefosine treated than untreated promastigotes [ 24 ]. Similarly, other anti-leishmanial agents such as chalcone and azasterols changed sterol profiles in L. amazonensis [ 25 , 26 ]. Drug resistance is associated with significantly altered sterol profiles (e.g.…”

Arginine and Polyamines Fate in Leishmania Infection

“…A rational strategy for the parasite control can be developed based on the identification of fundamental metabolic pathways of the parasite. New potential drug targets based on molecular and biochemical studies involving the following: protein kinases ( Naula et al, 2005 ), glycolytic enzymes ( Chawla et al, 2010 ), sterol synthesis ( Urbina et al, 2002 ; Lorente et al, 2004 ), purine salvage pathway ( Ullman and Carter, 1995 ; Landfear et al, 2004 ; Aoki et al, 2009 , 2016 ) and polyamine pathway ( Roberts et al, 2004 ; Reguera et al, 2005 ) have been described and could be used in future therapies ( Sharlow et al, 2009 ; Siqueira-Neto et al, 2010 ).…”

The efficacy of 2-nitrovinylfuran derivatives againstLeishmania in vitro and in vivo

“…Cytotoxicity against mammalian cells and selectivity index - Cytotoxicity assays were conducted as described elsewhere ( Lorente et al 2004 ). Briefly, plates were seeded with 100 µL of HeLa-KB cells (subline of the keratin-forming tumour cell line HeLa, ATCC, CCL-17(tm)) at 4 x 10 4 /mL in RPMI-1640 plus 10% heat-inactivated foetal calf serum and incubated at 37ºC in 5% CO 2 for 24 h. The overlay was removed and replaced by the test compounds in fresh medium at concentrations ranging from 30 µg/mL to 100 ng/mL in triplicate.…”